Insulin Receptor Substrate Proteins
Phosphoproteins
Insulin
Receptor, Insulin
Phosphorylation
Phosphatidylinositol 3-Kinases
Insulin Resistance
Signal Transduction
Intracellular Signaling Peptides and Proteins
Glucose
Tyrosine
Receptor, IGF Type 1
Proto-Oncogene Proteins c-akt
Phosphotyrosine
Substrate Specificity
Glucose Transporter Type 4
Adipocytes
Insulin-Like Growth Factor I
Phosphotransferases (Alcohol Group Acceptor)
Enzyme Activation
Molecular Sequence Data
Muscle, Skeletal
Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Chaperonin 10
3T3 Cells
Monosaccharide Transport Proteins
Protein-Serine-Threonine Kinases
Protein-Tyrosine Kinases
Protein Binding
GRB2 Adaptor Protein
Liver
Serine
CHO Cells
Proteins
Adipose Tissue
Binding Sites
Chaperonin 60
Proto-Oncogene Proteins
Diabetes Mellitus, Type 2
Cells, Cultured
Islets of Langerhans
Cricetinae
Protein Tyrosine Phosphatases
Precipitin Tests
Ribosomal Protein S6 Kinases
Androstadienes
Mice, Knockout
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Hyperinsulinism
Transfection
Muscle Proteins
Glucose Tolerance Test
src Homology Domains
Phosphotyrosine binding domains of Shc and insulin receptor substrate 1 recognize the NPXpY motif in a thermodynamically distinct manner. (1/1730)
Phosphotyrosine binding (PTB) domains of the adaptor protein Shc and insulin receptor substrate (IRS-1) interact with a distinct set of activated and tyrosine-phosphorylated cytokine and growth factor receptors and play important roles in mediating mitogenic signal transduction. By using the technique of isothermal titration calorimetry, we have studied the thermodynamics of binding of the Shc and IRS-1 PTB domains to tyrosine-phosphorylated NPXY-containing peptides derived from known receptor binding sites. The results showed that relative contributions of enthalpy and entropy to the free energy of binding are dependent on specific phosphopeptides. Binding of the Shc PTB domain to tyrosine-phosphorylated peptides from TrkA, epidermal growth factor, ErbB3, and insulin receptors is achieved via an overall entropy-driven reaction. On the other hand, recognition of the phosphopeptides of insulin and interleukin-4 receptors by the IRS-1 PTB domain is predominantly an enthalpy-driven process. Mutagenesis and amino acid substitution experiments showed that in addition to the tyrosine-phosphorylated NPXY motif, the PTB domains of Shc and IRS-1 prefer a large hydrophobic residue at pY-5 and a small hydrophobic residue at pY-1, respectively (where pY is phosphotyrosine). These results agree with the calculated solvent accessibility of these two key peptide residues in the PTB domain/peptide structures and support the notion that the PTB domains of Shc and IRS-1 employ functionally distinct mechanisms to recognize tyrosine-phosphorylated receptors. (+info)Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. (2/1730)
Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity. (+info)Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. (3/1730)
Mice deficient in C/EBP alpha have defective development of adipose tissue, but the precise role of C/EBP alpha has not been defined. Fibroblasts from C/EBP alpha(-/-) mice undergo adipose differentiation through expression and activation of PPAR gamma, though several clear defects are apparent. C/EBP alpha-deficient adipocytes accumulates less lipid, and they do not induce endogenous PPAR gamma, indicating that cross-regulation between C/EBP alpha and PPAR gamma is important in maintaining the differentiated state. The cells also show a complete absence of insulin-stimulated glucose transport, secondary to reduced gene expression and tyrosine phosphorylation for the insulin receptor and IRS-1. These results define multiple roles for C/EBP alpha in adipogenesis and show that cross-regulation between PPAR gamma and C/EBP alpha is a key component of the transcriptional control of this cell lineage. (+info)Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. (4/1730)
We investigated whether variability at the insulin receptor substrate (IRS)-2 locus plays a role in the etiology of early-onset autosomal dominant type 2 diabetes. By means of radiation hybrid mapping, we placed the human IRS-2 gene on 13q at 8.6 cRays from SHGC-37358. Linkage between diabetes and two polymorphic markers located in this region (D13S285 and D13S1295) was then evaluated in 29 families with early-onset autosomal dominant type 2 diabetes. Included were 220 individuals with diabetes, impaired glucose tolerance, or gestational diabetes (mean age at diabetes diagnosis 36 +/- 17 years) and 146 nondiabetic subjects. Overall, strongly negative logarithm of odds (LOD) scores for linkage with diabetes were obtained by multipoint parametric analysis (LOD score -45.4 at D13S285 and -40.9 at D13S1295). No significant evidence of linkage was obtained under the hypothesis of heterogeneity or by nonparametric methods. Fourteen pedigrees for which linkage could not be excluded (LOD score > -2.0) were screened for mutations in the IRS-2 coding region by dideoxy fingerprinting. However, no mutations segregating with diabetes could be detected in these families. These data indicate that IRS-2 is not a major gene for early-onset autosomal dominant type 2 diabetes, although a role of mutations in the promoter region cannot be excluded at this time. (+info)Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats. (5/1730)
To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia. (+info)Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. (6/1730)
The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed. (+info)Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. (7/1730)
Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been implicated as a negative regulator of insulin signaling. Prior studies have indicated that this negative regulation by protein kinase C involves the mitogen-activated protein kinase and phosphorylation of serine 612 in IRS-1. In the present studies, the negative regulation by platelet-derived growth factor (PDGF) was compared with that induced by endothelin-1, an activator of protein kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not require mitogen-activated protein kinase or the phosphorylation of serine 612. Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 662, and 731) were required for the negative regulation by PDGF. In addition, the PDGF-activated serine/threonine kinase called Akt was found to inhibit insulin signaling. Moreover, this inhibition required the same IRS-1 serine residues as the inhibition by PDGF. Finally, the negative regulatory effects of PDGF and Akt were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), one of the downstream targets of Akt. These studies implicate the phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative regulatory pathway for the insulin signaling cascade. (+info)Pertussis toxin-sensitive and insensitive intracellular signalling pathways in undifferentiated 3T3-L1 cells stimulated by insulin converge with phosphatidylinositol 3-kinase upstream of the Ras mitogen-activated protein kinase cascade. (8/1730)
We have previously reported that pertussis toxin (PTX)-sensitive GTP binding protein (G-protein) and phosphatidylinositol 3-kinase (PI 3-K) are involved in adipocyte differentiation of 3T3-L1 cells induced by insulin/dexamethasone/methylisobutyl xanthine. The aim of this study was to examine the effect of PTX on the tyrosine kinase cascade stimulated by insulin acting through insulin-like growth factor-I (IGF-I) receptors in undifferentiated 3T3-L1 cells. A high level of mitogen-activated protein kinase (MAPK) activation was sustained for up to 4 h after insulin treatment, and mobility shifted and tyrosine phosphorylated MAPK was also detected. MAPK kinase activity measured by the incorporation of 32P into kinase-negative recombinant MAPK was enhanced by insulin treatment. We previously discovered that insulin activates Ras and that this is mediated by wortmannin-sensitive PI 3-K. Tyrosine-phosphorylation of IRS-1 and Shc also occurred in response to insulin. Subsequently, we investigated the effects of PTX on the activation of these proteins by insulin. Interestingly, treating 3T3-L1 cells with PTX attenuates the activation by insulin of both the Ras-MAPK cascade and PI 3-K. In contrast, neither tyrosine-phosphorylation of IRS-1 and Shc nor the interaction between IRS-1 and PI 3-K is sensitive to PTX. However, activation of the Ras-MAPK cascade and tyrosine-phosphorylation of Shc by epidermal growth factor are insensitive to PTX. These results indicate that there is another pathway which regulates PI 3-K and Ras-MAPK, independent of the pathway mediated by IGF-I receptor kinase. These findings suggest that in 3T3-L1 fibroblasts, PTX-sensitive G-proteins cross-talk with the Ras-MAPK pathway via PI 3-K by insulin acting via IGF-I receptors. (+info)Insulin Receptor Substrate (IRS) proteins are a family of cytoplasmic signaling proteins that play a crucial role in the insulin signaling pathway. There are four main isoforms in humans, namely IRS-1, IRS-2, IRS-3, and IRS-4, which contain several conserved domains for interacting with various signaling molecules.
When insulin binds to its receptor, the intracellular tyrosine kinase domain of the receptor becomes activated and phosphorylates specific tyrosine residues on IRS proteins. This leads to the recruitment and activation of downstream effectors, such as PI3K and Grb2/SOS, which ultimately result in metabolic responses (e.g., glucose uptake, glycogen synthesis) and mitogenic responses (e.g., cell proliferation, differentiation).
Dysregulation of the IRS-mediated insulin signaling pathway has been implicated in several pathological conditions, including insulin resistance, type 2 diabetes, and certain types of cancer.
Phosphoproteins are proteins that have been post-translationally modified by the addition of a phosphate group (-PO3H2) onto specific amino acid residues, most commonly serine, threonine, or tyrosine. This process is known as phosphorylation and is mediated by enzymes called kinases. Phosphoproteins play crucial roles in various cellular processes such as signal transduction, cell cycle regulation, metabolism, and gene expression. The addition or removal of a phosphate group can activate or inhibit the function of a protein, thereby serving as a switch to control its activity. Phosphoproteins can be detected and quantified using techniques such as Western blotting, mass spectrometry, and immunofluorescence.
Insulin is a hormone produced by the beta cells of the pancreatic islets, primarily in response to elevated levels of glucose in the circulating blood. It plays a crucial role in regulating blood glucose levels and facilitating the uptake and utilization of glucose by peripheral tissues, such as muscle and adipose tissue, for energy production and storage. Insulin also inhibits glucose production in the liver and promotes the storage of excess glucose as glycogen or triglycerides.
Deficiency in insulin secretion or action leads to impaired glucose regulation and can result in conditions such as diabetes mellitus, characterized by chronic hyperglycemia and associated complications. Exogenous insulin is used as a replacement therapy in individuals with diabetes to help manage their blood glucose levels and prevent long-term complications.
An insulin receptor is a transmembrane protein found on the surface of cells, primarily in the liver, muscle, and adipose tissue. It plays a crucial role in regulating glucose metabolism in the body. When insulin binds to its receptor, it triggers a series of intracellular signaling events that promote the uptake and utilization of glucose by cells, as well as the storage of excess glucose as glycogen or fat.
Insulin receptors are composed of two extracellular alpha subunits and two transmembrane beta subunits, which are linked together by disulfide bonds. The binding of insulin to the alpha subunits activates the tyrosine kinase activity of the beta subunits, leading to the phosphorylation of intracellular proteins and the initiation of downstream signaling pathways.
Abnormalities in insulin receptor function or number can contribute to the development of insulin resistance and type 2 diabetes.
Phosphorylation is the process of adding a phosphate group (a molecule consisting of one phosphorus atom and four oxygen atoms) to a protein or other organic molecule, which is usually done by enzymes called kinases. This post-translational modification can change the function, localization, or activity of the target molecule, playing a crucial role in various cellular processes such as signal transduction, metabolism, and regulation of gene expression. Phosphorylation is reversible, and the removal of the phosphate group is facilitated by enzymes called phosphatases.
Phosphatidylinositol 3-Kinases (PI3Ks) are a family of enzymes that play a crucial role in intracellular signal transduction. They phosphorylate the 3-hydroxyl group of the inositol ring in phosphatidylinositol and its derivatives, which results in the production of second messengers that regulate various cellular processes such as cell growth, proliferation, differentiation, motility, and survival.
PI3Ks are divided into three classes based on their structure and substrate specificity. Class I PI3Ks are further subdivided into two categories: class IA and class IB. Class IA PI3Ks are heterodimers consisting of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85α, p85β, p55γ, or p50γ). They are primarily activated by receptor tyrosine kinases and G protein-coupled receptors. Class IB PI3Ks consist of a catalytic subunit (p110γ) and a regulatory subunit (p101 or p84/87). They are mainly activated by G protein-coupled receptors.
Dysregulation of PI3K signaling has been implicated in various human diseases, including cancer, diabetes, and autoimmune disorders. Therefore, PI3Ks have emerged as important targets for drug development in these areas.
Insulin resistance is a condition in which the body's cells become less responsive to insulin, a hormone produced by the pancreas that regulates blood sugar levels. In response to this decreased sensitivity, the pancreas produces more insulin to help glucose enter the cells. However, over time, the pancreas may not be able to keep up with the increased demand for insulin, leading to high levels of glucose in the blood and potentially resulting in type 2 diabetes, prediabetes, or other health issues such as metabolic syndrome, cardiovascular disease, and non-alcoholic fatty liver disease. Insulin resistance is often associated with obesity, physical inactivity, and genetic factors.
Signal transduction is the process by which a cell converts an extracellular signal, such as a hormone or neurotransmitter, into an intracellular response. This involves a series of molecular events that transmit the signal from the cell surface to the interior of the cell, ultimately resulting in changes in gene expression, protein activity, or metabolism.
The process typically begins with the binding of the extracellular signal to a receptor located on the cell membrane. This binding event activates the receptor, which then triggers a cascade of intracellular signaling molecules, such as second messengers, protein kinases, and ion channels. These molecules amplify and propagate the signal, ultimately leading to the activation or inhibition of specific cellular responses.
Signal transduction pathways are highly regulated and can be modulated by various factors, including other signaling molecules, post-translational modifications, and feedback mechanisms. Dysregulation of these pathways has been implicated in a variety of diseases, including cancer, diabetes, and neurological disorders.
Intracellular signaling peptides and proteins are molecules that play a crucial role in transmitting signals within cells, which ultimately lead to changes in cell behavior or function. These signals can originate from outside the cell (extracellular) or within the cell itself. Intracellular signaling molecules include various types of peptides and proteins, such as:
1. G-protein coupled receptors (GPCRs): These are seven-transmembrane domain receptors that bind to extracellular signaling molecules like hormones, neurotransmitters, or chemokines. Upon activation, they initiate a cascade of intracellular signals through G proteins and secondary messengers.
2. Receptor tyrosine kinases (RTKs): These are transmembrane receptors that bind to growth factors, cytokines, or hormones. Activation of RTKs leads to autophosphorylation of specific tyrosine residues, creating binding sites for intracellular signaling proteins such as adapter proteins, phosphatases, and enzymes like Ras, PI3K, and Src family kinases.
3. Second messenger systems: Intracellular second messengers are small molecules that amplify and propagate signals within the cell. Examples include cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG), inositol triphosphate (IP3), calcium ions (Ca2+), and nitric oxide (NO). These second messengers activate or inhibit various downstream effectors, leading to changes in cellular responses.
4. Signal transduction cascades: Intracellular signaling proteins often form complex networks of interacting molecules that relay signals from the plasma membrane to the nucleus. These cascades involve kinases (protein kinases A, B, C, etc.), phosphatases, and adapter proteins, which ultimately regulate gene expression, cell cycle progression, metabolism, and other cellular processes.
5. Ubiquitination and proteasome degradation: Intracellular signaling pathways can also control protein stability by modulating ubiquitin-proteasome degradation. E3 ubiquitin ligases recognize specific substrates and conjugate them with ubiquitin molecules, targeting them for proteasomal degradation. This process regulates the abundance of key signaling proteins and contributes to signal termination or amplification.
In summary, intracellular signaling pathways involve a complex network of interacting proteins that relay signals from the plasma membrane to various cellular compartments, ultimately regulating gene expression, metabolism, and other cellular processes. Dysregulation of these pathways can contribute to disease development and progression, making them attractive targets for therapeutic intervention.
Glucose is a simple monosaccharide (or single sugar) that serves as the primary source of energy for living organisms. It's a fundamental molecule in biology, often referred to as "dextrose" or "grape sugar." Glucose has the molecular formula C6H12O6 and is vital to the functioning of cells, especially those in the brain and nervous system.
In the body, glucose is derived from the digestion of carbohydrates in food, and it's transported around the body via the bloodstream to cells where it can be used for energy. Cells convert glucose into a usable form through a process called cellular respiration, which involves a series of metabolic reactions that generate adenosine triphosphate (ATP)—the main currency of energy in cells.
Glucose is also stored in the liver and muscles as glycogen, a polysaccharide (multiple sugar) that can be broken down back into glucose when needed for energy between meals or during physical activity. Maintaining appropriate blood glucose levels is crucial for overall health, and imbalances can lead to conditions such as diabetes mellitus.
Tyrosine is an non-essential amino acid, which means that it can be synthesized by the human body from another amino acid called phenylalanine. Its name is derived from the Greek word "tyros," which means cheese, as it was first isolated from casein, a protein found in cheese.
Tyrosine plays a crucial role in the production of several important substances in the body, including neurotransmitters such as dopamine, norepinephrine, and epinephrine, which are involved in various physiological processes, including mood regulation, stress response, and cognitive functions. It also serves as a precursor to melanin, the pigment responsible for skin, hair, and eye color.
In addition, tyrosine is involved in the structure of proteins and is essential for normal growth and development. Some individuals may require tyrosine supplementation if they have a genetic disorder that affects tyrosine metabolism or if they are phenylketonurics (PKU), who cannot metabolize phenylalanine, which can lead to elevated tyrosine levels in the blood. However, it is important to consult with a healthcare professional before starting any supplementation regimen.
IGF-1R (Insulin-like Growth Factor 1 Receptor) is a transmembrane receptor tyrosine kinase that plays a crucial role in intracellular signaling pathways related to cell growth, differentiation, and survival. IGF-1R is primarily activated by its ligands, IGF-1 (Insulin-like Growth Factor 1) and IGF-2 (Insulin-like Growth Factor 2). Upon binding of the ligand, IGF-1R undergoes autophosphorylation and initiates a cascade of intracellular signaling events, primarily through the PI3K/AKT and RAS/MAPK pathways. These signaling cascades ultimately regulate various cellular processes such as glucose metabolism, protein synthesis, DNA replication, and cell cycle progression. Dysregulation of IGF-1R has been implicated in several diseases, including cancer, diabetes, and growth disorders.
Protein-kinase B, also known as AKT, is a group of intracellular proteins that play a crucial role in various cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. The AKT family includes three isoforms: AKT1, AKT2, and AKT3, which are encoded by the genes PKBalpha, PKBbeta, and PKBgamma, respectively.
Proto-oncogene proteins c-AKT refer to the normal, non-mutated forms of these proteins that are involved in the regulation of cell growth and survival under physiological conditions. However, when these genes are mutated or overexpressed, they can become oncogenes, leading to uncontrolled cell growth and cancer development.
Activation of c-AKT occurs through a signaling cascade that begins with the binding of extracellular ligands such as insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) to their respective receptors on the cell surface. This triggers a series of phosphorylation events that ultimately lead to the activation of c-AKT, which then phosphorylates downstream targets involved in various cellular processes.
In summary, proto-oncogene proteins c-AKT are normal intracellular proteins that play essential roles in regulating cell growth and survival under physiological conditions. However, their dysregulation can contribute to cancer development and progression.
Phosphotyrosine is not a medical term per se, but rather a biochemical term used in the field of medicine and life sciences.
Phosphotyrosine is a post-translational modification of tyrosine residues in proteins, where a phosphate group is added to the hydroxyl side chain of tyrosine by protein kinases. This modification plays a crucial role in intracellular signaling pathways and regulates various cellular processes such as cell growth, differentiation, and apoptosis. Abnormalities in phosphotyrosine-mediated signaling have been implicated in several diseases, including cancer and diabetes.
Substrate specificity in the context of medical biochemistry and enzymology refers to the ability of an enzyme to selectively bind and catalyze a chemical reaction with a particular substrate (or a group of similar substrates) while discriminating against other molecules that are not substrates. This specificity arises from the three-dimensional structure of the enzyme, which has evolved to match the shape, charge distribution, and functional groups of its physiological substrate(s).
Substrate specificity is a fundamental property of enzymes that enables them to carry out highly selective chemical transformations in the complex cellular environment. The active site of an enzyme, where the catalysis takes place, has a unique conformation that complements the shape and charge distribution of its substrate(s). This ensures efficient recognition, binding, and conversion of the substrate into the desired product while minimizing unwanted side reactions with other molecules.
Substrate specificity can be categorized as:
1. Absolute specificity: An enzyme that can only act on a single substrate or a very narrow group of structurally related substrates, showing no activity towards any other molecule.
2. Group specificity: An enzyme that prefers to act on a particular functional group or class of compounds but can still accommodate minor structural variations within the substrate.
3. Broad or promiscuous specificity: An enzyme that can act on a wide range of structurally diverse substrates, albeit with varying catalytic efficiencies.
Understanding substrate specificity is crucial for elucidating enzymatic mechanisms, designing drugs that target specific enzymes or pathways, and developing biotechnological applications that rely on the controlled manipulation of enzyme activities.
Glucose Transporter Type 4 (GLUT4) is a type of glucose transporter protein that plays a crucial role in regulating insulin-mediated glucose uptake into cells, particularly in muscle and fat tissues. GLUT4 is primarily located in intracellular vesicles within these cell types and moves to the plasma membrane upon stimulation by insulin or muscle contraction, facilitating the influx of glucose into the cell. Dysfunction in GLUT4 regulation has been implicated in various metabolic disorders, including type 2 diabetes and insulin resistance.
Adipocytes are specialized cells that comprise adipose tissue, also known as fat tissue. They are responsible for storing energy in the form of lipids, particularly triglycerides, and releasing energy when needed through a process called lipolysis. There are two main types of adipocytes: white adipocytes and brown adipocytes. White adipocytes primarily store energy, while brown adipocytes dissipate energy as heat through the action of uncoupling protein 1 (UCP1).
In addition to their role in energy metabolism, adipocytes also secrete various hormones and signaling molecules that contribute to whole-body homeostasis. These include leptin, adiponectin, resistin, and inflammatory cytokines. Dysregulation of adipocyte function has been implicated in the development of obesity, insulin resistance, type 2 diabetes, and cardiovascular disease.
Insulin-like growth factor I (IGF-I) is a hormone that plays a crucial role in growth and development. It is a small protein with structural and functional similarity to insulin, hence the name "insulin-like." IGF-I is primarily produced in the liver under the regulation of growth hormone (GH).
IGF-I binds to its specific receptor, the IGF-1 receptor, which is widely expressed throughout the body. This binding activates a signaling cascade that promotes cell proliferation, differentiation, and survival. In addition, IGF-I has anabolic effects on various tissues, including muscle, bone, and cartilage, contributing to their growth and maintenance.
IGF-I is essential for normal growth during childhood and adolescence, and it continues to play a role in maintaining tissue homeostasis throughout adulthood. Abnormal levels of IGF-I have been associated with various medical conditions, such as growth disorders, diabetes, and certain types of cancer.
Enzyme activation refers to the process by which an enzyme becomes biologically active and capable of carrying out its specific chemical or biological reaction. This is often achieved through various post-translational modifications, such as proteolytic cleavage, phosphorylation, or addition of cofactors or prosthetic groups to the enzyme molecule. These modifications can change the conformation or structure of the enzyme, exposing or creating a binding site for the substrate and allowing the enzymatic reaction to occur.
For example, in the case of proteolytic cleavage, an inactive precursor enzyme, known as a zymogen, is cleaved into its active form by a specific protease. This is seen in enzymes such as trypsin and chymotrypsin, which are initially produced in the pancreas as inactive precursors called trypsinogen and chymotrypsinogen, respectively. Once they reach the small intestine, they are activated by enteropeptidase, a protease that cleaves a specific peptide bond, releasing the active enzyme.
Phosphorylation is another common mechanism of enzyme activation, where a phosphate group is added to a specific serine, threonine, or tyrosine residue on the enzyme by a protein kinase. This modification can alter the conformation of the enzyme and create a binding site for the substrate, allowing the enzymatic reaction to occur.
Enzyme activation is a crucial process in many biological pathways, as it allows for precise control over when and where specific reactions take place. It also provides a mechanism for regulating enzyme activity in response to various signals and stimuli, such as hormones, neurotransmitters, or changes in the intracellular environment.
Molecular sequence data refers to the specific arrangement of molecules, most commonly nucleotides in DNA or RNA, or amino acids in proteins, that make up a biological macromolecule. This data is generated through laboratory techniques such as sequencing, and provides information about the exact order of the constituent molecules. This data is crucial in various fields of biology, including genetics, evolution, and molecular biology, allowing for comparisons between different organisms, identification of genetic variations, and studies of gene function and regulation.
Skeletal muscle, also known as striated or voluntary muscle, is a type of muscle that is attached to bones by tendons or aponeuroses and functions to produce movements and support the posture of the body. It is composed of long, multinucleated fibers that are arranged in parallel bundles and are characterized by alternating light and dark bands, giving them a striped appearance under a microscope. Skeletal muscle is under voluntary control, meaning that it is consciously activated through signals from the nervous system. It is responsible for activities such as walking, running, jumping, and lifting objects.
Adaptor proteins are a type of protein that play a crucial role in intracellular signaling pathways by serving as a link between different components of the signaling complex. Specifically, "signal transducing adaptor proteins" refer to those adaptor proteins that are involved in signal transduction processes, where they help to transmit signals from the cell surface receptors to various intracellular effectors. These proteins typically contain modular domains that allow them to interact with multiple partners, thereby facilitating the formation of large signaling complexes and enabling the integration of signals from different pathways.
Signal transducing adaptor proteins can be classified into several families based on their structural features, including the Src homology 2 (SH2) domain, the Src homology 3 (SH3) domain, and the phosphotyrosine-binding (PTB) domain. These domains enable the adaptor proteins to recognize and bind to specific motifs on other signaling molecules, such as receptor tyrosine kinases, G protein-coupled receptors, and cytokine receptors.
One well-known example of a signal transducing adaptor protein is the growth factor receptor-bound protein 2 (Grb2), which contains an SH2 domain that binds to phosphotyrosine residues on activated receptor tyrosine kinases. Grb2 also contains an SH3 domain that interacts with proline-rich motifs on other signaling proteins, such as the guanine nucleotide exchange factor SOS. This interaction facilitates the activation of the Ras small GTPase and downstream signaling pathways involved in cell growth, differentiation, and survival.
Overall, signal transducing adaptor proteins play a critical role in regulating various cellular processes by modulating intracellular signaling pathways in response to extracellular stimuli. Dysregulation of these proteins has been implicated in various diseases, including cancer and inflammatory disorders.
An amino acid sequence is the specific order of amino acids in a protein or peptide molecule, formed by the linking of the amino group (-NH2) of one amino acid to the carboxyl group (-COOH) of another amino acid through a peptide bond. The sequence is determined by the genetic code and is unique to each type of protein or peptide. It plays a crucial role in determining the three-dimensional structure and function of proteins.
Chaperonin 10, also known as CPN10 or HSP10 (heat shock protein 10), is a small heat shock protein that functions as a component of the chaperone complex in the mitochondria. It assists in the folding and assembly of proteins, particularly during stressful conditions when protein misfolding is more likely to occur. Chaperonin 10 forms a complex with Chaperonin 60 (CPN60 or HSP60) to facilitate the proper folding of imported mitochondrial proteins. The chaperonin complex provides a protected environment for protein folding, allowing hydrophobic regions to be exposed without aggregating with other unfolded proteins in the cell.
3T3 cells are a type of cell line that is commonly used in scientific research. The name "3T3" is derived from the fact that these cells were developed by treating mouse embryo cells with a chemical called trypsin and then culturing them in a flask at a temperature of 37 degrees Celsius.
Specifically, 3T3 cells are a type of fibroblast, which is a type of cell that is responsible for producing connective tissue in the body. They are often used in studies involving cell growth and proliferation, as well as in toxicity tests and drug screening assays.
One particularly well-known use of 3T3 cells is in the 3T3-L1 cell line, which is a subtype of 3T3 cells that can be differentiated into adipocytes (fat cells) under certain conditions. These cells are often used in studies of adipose tissue biology and obesity.
It's important to note that because 3T3 cells are a type of immortalized cell line, they do not always behave exactly the same way as primary cells (cells that are taken directly from a living organism). As such, researchers must be careful when interpreting results obtained using 3T3 cells and consider any potential limitations or artifacts that may arise due to their use.
In the context of medicine and pharmacology, "kinetics" refers to the study of how a drug moves throughout the body, including its absorption, distribution, metabolism, and excretion (often abbreviated as ADME). This field is called "pharmacokinetics."
1. Absorption: This is the process of a drug moving from its site of administration into the bloodstream. Factors such as the route of administration (e.g., oral, intravenous, etc.), formulation, and individual physiological differences can affect absorption.
2. Distribution: Once a drug is in the bloodstream, it gets distributed throughout the body to various tissues and organs. This process is influenced by factors like blood flow, protein binding, and lipid solubility of the drug.
3. Metabolism: Drugs are often chemically modified in the body, typically in the liver, through processes known as metabolism. These changes can lead to the formation of active or inactive metabolites, which may then be further distributed, excreted, or undergo additional metabolic transformations.
4. Excretion: This is the process by which drugs and their metabolites are eliminated from the body, primarily through the kidneys (urine) and the liver (bile).
Understanding the kinetics of a drug is crucial for determining its optimal dosing regimen, potential interactions with other medications or foods, and any necessary adjustments for special populations like pediatric or geriatric patients, or those with impaired renal or hepatic function.
A cell line is a culture of cells that are grown in a laboratory for use in research. These cells are usually taken from a single cell or group of cells, and they are able to divide and grow continuously in the lab. Cell lines can come from many different sources, including animals, plants, and humans. They are often used in scientific research to study cellular processes, disease mechanisms, and to test new drugs or treatments. Some common types of human cell lines include HeLa cells (which come from a cancer patient named Henrietta Lacks), HEK293 cells (which come from embryonic kidney cells), and HUVEC cells (which come from umbilical vein endothelial cells). It is important to note that cell lines are not the same as primary cells, which are cells that are taken directly from a living organism and have not been grown in the lab.
Monosaccharide transport proteins are a type of membrane transport protein that facilitate the passive or active transport of monosaccharides, such as glucose, fructose, and galactose, across cell membranes. These proteins play a crucial role in the absorption, distribution, and metabolism of carbohydrates in the body.
There are two main types of monosaccharide transport proteins: facilitated diffusion transporters and active transporters. Facilitated diffusion transporters, also known as glucose transporters (GLUTs), passively transport monosaccharides down their concentration gradient without the need for energy. In contrast, active transporters, such as the sodium-glucose cotransporter (SGLT), use energy in the form of ATP to actively transport monosaccharides against their concentration gradient.
Monosaccharide transport proteins are found in various tissues throughout the body, including the intestines, kidneys, liver, and brain. They play a critical role in maintaining glucose homeostasis by regulating the uptake and release of glucose into and out of cells. Dysfunction of these transporters has been implicated in several diseases, such as diabetes, cancer, and neurological disorders.
Protein-Serine-Threonine Kinases (PSTKs) are a type of protein kinase that catalyzes the transfer of a phosphate group from ATP to the hydroxyl side chains of serine or threonine residues on target proteins. This phosphorylation process plays a crucial role in various cellular signaling pathways, including regulation of metabolism, gene expression, cell cycle progression, and apoptosis. PSTKs are involved in many physiological and pathological processes, and their dysregulation has been implicated in several diseases, such as cancer, diabetes, and neurodegenerative disorders.
Protein-Tyrosine Kinases (PTKs) are a type of enzyme that plays a crucial role in various cellular functions, including signal transduction, cell growth, differentiation, and metabolism. They catalyze the transfer of a phosphate group from ATP to the tyrosine residues of proteins, thereby modifying their activity, localization, or interaction with other molecules.
PTKs can be divided into two main categories: receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs). RTKs are transmembrane proteins that become activated upon binding to specific ligands, such as growth factors or hormones. NRTKs, on the other hand, are intracellular enzymes that can be activated by various signals, including receptor-mediated signaling and intracellular messengers.
Dysregulation of PTK activity has been implicated in several diseases, such as cancer, diabetes, and inflammatory disorders. Therefore, PTKs are important targets for drug development and therapy.
Deoxyglucose is a glucose molecule that has had one oxygen atom removed, resulting in the absence of a hydroxyl group (-OH) at the 2' position of the carbon chain. It is used in research and medical settings as a metabolic tracer to study glucose uptake and metabolism in cells and organisms.
Deoxyglucose can be taken up by cells through glucose transporters, but it cannot be further metabolized by glycolysis or other glucose-utilizing pathways. This leads to the accumulation of deoxyglucose within the cell, which can interfere with normal cellular processes and cause toxicity in high concentrations.
In medical research, deoxyglucose is sometimes labeled with radioactive isotopes such as carbon-14 or fluorine-18 to create radiolabeled deoxyglucose (FDG), which can be used in positron emission tomography (PET) scans to visualize and measure glucose uptake in tissues. This technique is commonly used in cancer imaging, as tumors often have increased glucose metabolism compared to normal tissue.
Protein binding, in the context of medical and biological sciences, refers to the interaction between a protein and another molecule (known as the ligand) that results in a stable complex. This process is often reversible and can be influenced by various factors such as pH, temperature, and concentration of the involved molecules.
In clinical chemistry, protein binding is particularly important when it comes to drugs, as many of them bind to proteins (especially albumin) in the bloodstream. The degree of protein binding can affect a drug's distribution, metabolism, and excretion, which in turn influence its therapeutic effectiveness and potential side effects.
Protein-bound drugs may be less available for interaction with their target tissues, as only the unbound or "free" fraction of the drug is active. Therefore, understanding protein binding can help optimize dosing regimens and minimize adverse reactions.
The GRB2 (Growth Factor Receptor-Bound Protein 2) adaptor protein is a cytoplasmic signaling molecule that plays a crucial role in intracellular signal transduction pathways, particularly those involved in cell growth, differentiation, and survival. It acts as a molecular adapter or scaffold, facilitating the interaction between various proteins to form multi-protein complexes and propagate signals from activated receptor tyrosine kinases (RTKs) to downstream effectors.
GRB2 contains several functional domains, including an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The SH2 domain is responsible for binding to specific phosphotyrosine residues on activated RTKs or other adaptor proteins, while the SH3 domains mediate interactions with proline-rich sequences in partner proteins.
Once GRB2 binds to an activated RTK, it recruits and activates the guanine nucleotide exchange factor SOS (Son of Sevenless), which in turn activates the RAS GTPase. Activated RAS then initiates a signaling cascade involving various kinases such as Raf, MEK, and ERK, ultimately leading to changes in gene expression and cellular responses.
In summary, GRB2 is an essential adaptor protein that facilitates the transmission of signals from activated growth factor receptors to downstream effectors, playing a critical role in regulating various cellular processes.
Insulin antagonists are drugs or substances that interfere with the action of insulin, a hormone that regulates blood sugar levels in the body. These agents can either block the binding of insulin to its receptors on cell surfaces or inhibit the signaling pathways that mediate insulin's effects.
Examples of insulin antagonists include some glucocorticoids, thyroid hormones, and certain medications used to treat diabetes such as sulfonylureas and meglitinides. These drugs can increase blood sugar levels by stimulating the release of glucose from the liver or impairing the ability of insulin to promote glucose uptake in muscle and fat tissues.
It's important to note that while insulin antagonists can be useful in managing certain medical conditions, they can also contribute to the development of insulin resistance and diabetes if used inappropriately or in excess.
The liver is a large, solid organ located in the upper right portion of the abdomen, beneath the diaphragm and above the stomach. It plays a vital role in several bodily functions, including:
1. Metabolism: The liver helps to metabolize carbohydrates, fats, and proteins from the food we eat into energy and nutrients that our bodies can use.
2. Detoxification: The liver detoxifies harmful substances in the body by breaking them down into less toxic forms or excreting them through bile.
3. Synthesis: The liver synthesizes important proteins, such as albumin and clotting factors, that are necessary for proper bodily function.
4. Storage: The liver stores glucose, vitamins, and minerals that can be released when the body needs them.
5. Bile production: The liver produces bile, a digestive juice that helps to break down fats in the small intestine.
6. Immune function: The liver plays a role in the immune system by filtering out bacteria and other harmful substances from the blood.
Overall, the liver is an essential organ that plays a critical role in maintaining overall health and well-being.
Hypoglycemic agents are a class of medications that are used to lower blood glucose levels in the treatment of diabetes mellitus. These medications work by increasing insulin sensitivity, stimulating insulin release from the pancreas, or inhibiting glucose production in the liver. Examples of hypoglycemic agents include sulfonylureas, meglitinides, biguanides, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. It's important to note that the term "hypoglycemic" refers to a condition of abnormally low blood glucose levels, but in this context, the term is used to describe agents that are used to treat high blood glucose levels (hyperglycemia) associated with diabetes.
Serine is an amino acid, which is a building block of proteins. More specifically, it is a non-essential amino acid, meaning that the body can produce it from other compounds, and it does not need to be obtained through diet. Serine plays important roles in the body, such as contributing to the formation of the protective covering of nerve fibers (myelin sheath), helping to synthesize another amino acid called tryptophan, and taking part in the metabolism of fatty acids. It is also involved in the production of muscle tissues, the immune system, and the forming of cell structures. Serine can be found in various foods such as soy, eggs, cheese, meat, peanuts, lentils, and many others.
CHO cells, or Chinese Hamster Ovary cells, are a type of immortalized cell line that are commonly used in scientific research and biotechnology. They were originally derived from the ovaries of a female Chinese hamster (Cricetulus griseus) in the 1950s.
CHO cells have several characteristics that make them useful for laboratory experiments. They can grow and divide indefinitely under appropriate conditions, which allows researchers to culture large quantities of them for study. Additionally, CHO cells are capable of expressing high levels of recombinant proteins, making them a popular choice for the production of therapeutic drugs, vaccines, and other biologics.
In particular, CHO cells have become a workhorse in the field of biotherapeutics, with many approved monoclonal antibody-based therapies being produced using these cells. The ability to genetically modify CHO cells through various methods has further expanded their utility in research and industrial applications.
It is important to note that while CHO cells are widely used in scientific research, they may not always accurately represent human cell behavior or respond to drugs and other compounds in the same way as human cells do. Therefore, results obtained using CHO cells should be validated in more relevant systems when possible.
Proteins are complex, large molecules that play critical roles in the body's functions. They are made up of amino acids, which are organic compounds that are the building blocks of proteins. Proteins are required for the structure, function, and regulation of the body's tissues and organs. They are essential for the growth, repair, and maintenance of body tissues, and they play a crucial role in many biological processes, including metabolism, immune response, and cellular signaling. Proteins can be classified into different types based on their structure and function, such as enzymes, hormones, antibodies, and structural proteins. They are found in various foods, especially animal-derived products like meat, dairy, and eggs, as well as plant-based sources like beans, nuts, and grains.
Adipose tissue, also known as fatty tissue, is a type of connective tissue that is composed mainly of adipocytes (fat cells). It is found throughout the body, but is particularly abundant in the abdominal cavity, beneath the skin, and around organs such as the heart and kidneys.
Adipose tissue serves several important functions in the body. One of its primary roles is to store energy in the form of fat, which can be mobilized and used as an energy source during periods of fasting or exercise. Adipose tissue also provides insulation and cushioning for the body, and produces hormones that help regulate metabolism, appetite, and reproductive function.
There are two main types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is the more common form and is responsible for storing energy as fat. BAT, on the other hand, contains a higher number of mitochondria and is involved in heat production and energy expenditure.
Excessive accumulation of adipose tissue can lead to obesity, which is associated with an increased risk of various health problems such as diabetes, heart disease, and certain types of cancer.
In the context of medical and biological sciences, a "binding site" refers to a specific location on a protein, molecule, or cell where another molecule can attach or bind. This binding interaction can lead to various functional changes in the original protein or molecule. The other molecule that binds to the binding site is often referred to as a ligand, which can be a small molecule, ion, or even another protein.
The binding between a ligand and its target binding site can be specific and selective, meaning that only certain ligands can bind to particular binding sites with high affinity. This specificity plays a crucial role in various biological processes, such as signal transduction, enzyme catalysis, or drug action.
In the case of drug development, understanding the location and properties of binding sites on target proteins is essential for designing drugs that can selectively bind to these sites and modulate protein function. This knowledge can help create more effective and safer therapeutic options for various diseases.
Chaperonin 60, also known as CPN60 or HSP60 (heat shock protein 60), is a type of molecular chaperone found in the mitochondria of eukaryotic cells. Molecular chaperones are proteins that assist in the proper folding and assembly of other proteins. Chaperonin 60 is a member of the HSP (heat shock protein) family, which are proteins that are upregulated in response to stressful conditions such as heat shock or oxidative stress.
Chaperonin 60 forms a large complex with a barrel-shaped structure that provides a protected environment for unfolded or misfolded proteins to fold properly. The protein substrate is bound inside the central cavity of the chaperonin complex, and then undergoes a series of conformational changes that facilitate its folding. Chaperonin 60 has been shown to play important roles in mitochondrial protein import, folding, and assembly, as well as in the regulation of apoptosis (programmed cell death).
Defects in chaperonin 60 have been linked to a variety of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer.
Proto-oncogene proteins are normal cellular proteins that play crucial roles in various cellular processes, such as signal transduction, cell cycle regulation, and apoptosis (programmed cell death). They are involved in the regulation of cell growth, differentiation, and survival under physiological conditions.
When proto-oncogene proteins undergo mutations or aberrations in their expression levels, they can transform into oncogenic forms, leading to uncontrolled cell growth and division. These altered proteins are then referred to as oncogene products or oncoproteins. Oncogenic mutations can occur due to various factors, including genetic predisposition, environmental exposures, and aging.
Examples of proto-oncogene proteins include:
1. Ras proteins: Involved in signal transduction pathways that regulate cell growth and differentiation. Activating mutations in Ras genes are found in various human cancers.
2. Myc proteins: Regulate gene expression related to cell cycle progression, apoptosis, and metabolism. Overexpression of Myc proteins is associated with several types of cancer.
3. EGFR (Epidermal Growth Factor Receptor): A transmembrane receptor tyrosine kinase that regulates cell proliferation, survival, and differentiation. Mutations or overexpression of EGFR are linked to various malignancies, such as lung cancer and glioblastoma.
4. Src family kinases: Intracellular tyrosine kinases that regulate signal transduction pathways involved in cell proliferation, survival, and migration. Dysregulation of Src family kinases is implicated in several types of cancer.
5. Abl kinases: Cytoplasmic tyrosine kinases that regulate various cellular processes, including cell growth, differentiation, and stress responses. Aberrant activation of Abl kinases, as seen in chronic myelogenous leukemia (CML), leads to uncontrolled cell proliferation.
Understanding the roles of proto-oncogene proteins and their dysregulation in cancer development is essential for developing targeted cancer therapies that aim to inhibit or modulate these aberrant signaling pathways.
Diabetes Mellitus, Type 2 is a metabolic disorder characterized by high blood glucose (or sugar) levels resulting from the body's inability to produce sufficient amounts of insulin or effectively use the insulin it produces. This form of diabetes usually develops gradually over several years and is often associated with older age, obesity, physical inactivity, family history of diabetes, and certain ethnicities.
In Type 2 diabetes, the body's cells become resistant to insulin, meaning they don't respond properly to the hormone. As a result, the pancreas produces more insulin to help glucose enter the cells. Over time, the pancreas can't keep up with the increased demand, leading to high blood glucose levels and diabetes.
Type 2 diabetes is managed through lifestyle modifications such as weight loss, regular exercise, and a healthy diet. Medications, including insulin therapy, may also be necessary to control blood glucose levels and prevent long-term complications associated with the disease, such as heart disease, nerve damage, kidney damage, and vision loss.
"Cells, cultured" is a medical term that refers to cells that have been removed from an organism and grown in controlled laboratory conditions outside of the body. This process is called cell culture and it allows scientists to study cells in a more controlled and accessible environment than they would have inside the body. Cultured cells can be derived from a variety of sources, including tissues, organs, or fluids from humans, animals, or cell lines that have been previously established in the laboratory.
Cell culture involves several steps, including isolation of the cells from the tissue, purification and characterization of the cells, and maintenance of the cells in appropriate growth conditions. The cells are typically grown in specialized media that contain nutrients, growth factors, and other components necessary for their survival and proliferation. Cultured cells can be used for a variety of purposes, including basic research, drug development and testing, and production of biological products such as vaccines and gene therapies.
It is important to note that cultured cells may behave differently than they do in the body, and results obtained from cell culture studies may not always translate directly to human physiology or disease. Therefore, it is essential to validate findings from cell culture experiments using additional models and ultimately in clinical trials involving human subjects.
The Islets of Langerhans are clusters of specialized cells within the pancreas, an organ located behind the stomach. These islets are named after Paul Langerhans, who first identified them in 1869. They constitute around 1-2% of the total mass of the pancreas and are distributed throughout its substance.
The Islets of Langerhans contain several types of cells, including:
1. Alpha (α) cells: These produce and release glucagon, a hormone that helps to regulate blood sugar levels by promoting the conversion of glycogen to glucose in the liver when blood sugar levels are low.
2. Beta (β) cells: These produce and release insulin, a hormone that promotes the uptake and utilization of glucose by cells throughout the body, thereby lowering blood sugar levels.
3. Delta (δ) cells: These produce and release somatostatin, a hormone that inhibits the release of both insulin and glucagon and helps regulate their secretion in response to changing blood sugar levels.
4. PP cells (gamma or γ cells): These produce and release pancreatic polypeptide, which plays a role in regulating digestive enzyme secretion and gastrointestinal motility.
Dysfunction of the Islets of Langerhans can lead to various endocrine disorders, such as diabetes mellitus, where insulin-producing beta cells are damaged or destroyed, leading to impaired blood sugar regulation.
Cricetinae is a subfamily of rodents that includes hamsters, gerbils, and relatives. These small mammals are characterized by having short limbs, compact bodies, and cheek pouches for storing food. They are native to various parts of the world, particularly in Europe, Asia, and Africa. Some species are popular pets due to their small size, easy care, and friendly nature. In a medical context, understanding the biology and behavior of Cricetinae species can be important for individuals who keep them as pets or for researchers studying their physiology.
Protein Tyrosine Phosphatases (PTPs) are a group of enzymes that play a crucial role in the regulation of various cellular processes, including cell growth, differentiation, and signal transduction. PTPs function by removing phosphate groups from tyrosine residues on proteins, thereby counteracting the effects of tyrosine kinases, which add phosphate groups to tyrosine residues to activate proteins.
PTPs are classified into several subfamilies based on their structure and function, including classical PTPs, dual-specificity PTPs (DSPs), and low molecular weight PTPs (LMW-PTPs). Each subfamily has distinct substrate specificities and regulatory mechanisms.
Classical PTPs are further divided into receptor-like PTPs (RPTPs) and non-receptor PTPs (NRPTPs). RPTPs contain a transmembrane domain and extracellular regions that mediate cell-cell interactions, while NRPTPs are soluble enzymes located in the cytoplasm.
DSPs can dephosphorylate both tyrosine and serine/threonine residues on proteins and play a critical role in regulating various signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway.
LMW-PTPs are a group of small molecular weight PTPs that localize to different cellular compartments, such as the endoplasmic reticulum and mitochondria, and regulate various cellular processes, including protein folding and apoptosis.
Overall, PTPs play a critical role in maintaining the balance of phosphorylation and dephosphorylation events in cells, and dysregulation of PTP activity has been implicated in various diseases, including cancer, diabetes, and neurological disorders.
A precipitin test is a type of immunodiagnostic test used to detect and measure the presence of specific antibodies or antigens in a patient's serum. The test is based on the principle of antigen-antibody interaction, where the addition of an antigen to a solution containing its corresponding antibody results in the formation of an insoluble immune complex known as a precipitin.
In this test, a small amount of the patient's serum is added to a solution containing a known antigen or antibody. If the patient has antibodies or antigens that correspond to the added reagent, they will bind and form a visible precipitate. The size and density of the precipitate can be used to quantify the amount of antibody or antigen present in the sample.
Precipitin tests are commonly used in the diagnosis of various infectious diseases, autoimmune disorders, and allergies. They can also be used in forensic science to identify biological samples. However, they have largely been replaced by more modern immunological techniques such as enzyme-linked immunosorbent assays (ELISAs) and radioimmunoassays (RIAs).
Ribosomal Protein S6 Kinases (RSKs) are a family of serine/threonine protein kinases that play a crucial role in the regulation of cell growth, proliferation, and survival. They are so named because they phosphorylate and regulate the function of the ribosomal protein S6, which is a component of the 40S ribosomal subunit involved in protein synthesis.
RSKs are activated by various signals, including growth factors, hormones, and mitogens, through a cascade of phosphorylation events involving several upstream kinases such as MAPK/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK). Once activated, RSKs phosphorylate a wide range of downstream targets, including transcription factors, regulators of translation, and cytoskeletal proteins, thereby modulating their activities and functions.
There are four isoforms of RSKs in humans, namely RSK1, RSK2, RSK3, and RSK4, which share a common structural organization and functional domains, including an N-terminal kinase domain, a C-terminal kinase domain, and a linker region that contains several regulatory motifs. Dysregulation of RSKs has been implicated in various pathological conditions, including cancer, cardiovascular diseases, neurological disorders, and diabetes, making them attractive targets for therapeutic intervention.
Androstadienes are a class of steroid hormones that are derived from androstenedione, which is a weak male sex hormone. Androstadienes include various compounds such as androstadiene-3,17-dione and androstanedione, which are intermediate products in the biosynthesis of more potent androgens like testosterone and dihydrotestosterone.
Androstadienes are present in both males and females but are found in higher concentrations in men. They can be detected in various bodily fluids, including blood, urine, sweat, and semen. In addition to their role in steroid hormone synthesis, androstadienes have been studied for their potential use as biomarkers of physiological processes and disease states.
It's worth noting that androstadienes are sometimes referred to as "androstenes" in the literature, although this term can also refer to other related compounds.
Recombinant proteins are artificially created proteins produced through the use of recombinant DNA technology. This process involves combining DNA molecules from different sources to create a new set of genes that encode for a specific protein. The resulting recombinant protein can then be expressed, purified, and used for various applications in research, medicine, and industry.
Recombinant proteins are widely used in biomedical research to study protein function, structure, and interactions. They are also used in the development of diagnostic tests, vaccines, and therapeutic drugs. For example, recombinant insulin is a common treatment for diabetes, while recombinant human growth hormone is used to treat growth disorders.
The production of recombinant proteins typically involves the use of host cells, such as bacteria, yeast, or mammalian cells, which are engineered to express the desired protein. The host cells are transformed with a plasmid vector containing the gene of interest, along with regulatory elements that control its expression. Once the host cells are cultured and the protein is expressed, it can be purified using various chromatography techniques.
Overall, recombinant proteins have revolutionized many areas of biology and medicine, enabling researchers to study and manipulate proteins in ways that were previously impossible.
A "knockout" mouse is a genetically engineered mouse in which one or more genes have been deleted or "knocked out" using molecular biology techniques. This allows researchers to study the function of specific genes and their role in various biological processes, as well as potential associations with human diseases. The mice are generated by introducing targeted DNA modifications into embryonic stem cells, which are then used to create a live animal. Knockout mice have been widely used in biomedical research to investigate gene function, disease mechanisms, and potential therapeutic targets.
Protein Tyrosine Phosphatase, Non-Receptor Type 1 (PTPN1) is a type of enzyme that belongs to the protein tyrosine phosphatase (PTP) family. PTPs play crucial roles in regulating various cellular processes by removing phosphate groups from phosphorylated tyrosine residues on proteins, thereby controlling the activity of many proteins involved in signal transduction pathways.
PTPN1, also known as PTP1B, is a non-receptor type PTP that is localized to the endoplasmic reticulum and cytosol of cells. It has been extensively studied due to its important role in regulating various cellular signaling pathways, including those involved in metabolism, cell growth, differentiation, and survival.
PTPN1 dephosphorylates several key signaling molecules, such as the insulin receptor, epidermal growth factor receptor (EGFR), and Janus kinase 2 (JAK2). By negatively regulating these signaling pathways, PTPN1 acts as a tumor suppressor and plays a role in preventing excessive cell growth and survival. However, dysregulation of PTPN1 has been implicated in various diseases, including diabetes, obesity, and cancer.
Hyperinsulinism is a medical condition characterized by an excess production and release of insulin from the pancreas. Insulin is a hormone that helps regulate blood sugar levels by allowing cells in the body to take in sugar (glucose) for energy or storage. In hyperinsulinism, the increased insulin levels can cause low blood sugar (hypoglycemia), which can lead to symptoms such as sweating, shaking, confusion, and in severe cases, seizures or loss of consciousness.
There are several types of hyperinsulinism, including congenital forms that are present at birth and acquired forms that develop later in life. Congenital hyperinsulinism is often caused by genetic mutations that affect the way insulin is produced or released from the pancreas. Acquired hyperinsulinism can be caused by factors such as certain medications, hormonal disorders, or tumors of the pancreas.
Treatment for hyperinsulinism depends on the underlying cause and severity of the condition. Treatment options may include dietary changes, medication to reduce insulin secretion, or surgery to remove part or all of the pancreas.
Transfection is a term used in molecular biology that refers to the process of deliberately introducing foreign genetic material (DNA, RNA or artificial gene constructs) into cells. This is typically done using chemical or physical methods, such as lipofection or electroporation. Transfection is widely used in research and medical settings for various purposes, including studying gene function, producing proteins, developing gene therapies, and creating genetically modified organisms. It's important to note that transfection is different from transduction, which is the process of introducing genetic material into cells using viruses as vectors.
Muscle proteins are a type of protein that are found in muscle tissue and are responsible for providing structure, strength, and functionality to muscles. The two major types of muscle proteins are:
1. Contractile proteins: These include actin and myosin, which are responsible for the contraction and relaxation of muscles. They work together to cause muscle movement by sliding along each other and shortening the muscle fibers.
2. Structural proteins: These include titin, nebulin, and desmin, which provide structural support and stability to muscle fibers. Titin is the largest protein in the human body and acts as a molecular spring that helps maintain the integrity of the sarcomere (the basic unit of muscle contraction). Nebulin helps regulate the length of the sarcomere, while desmin forms a network of filaments that connects adjacent muscle fibers together.
Overall, muscle proteins play a critical role in maintaining muscle health and function, and their dysregulation can lead to various muscle-related disorders such as muscular dystrophy, myopathies, and sarcopenia.
Blood glucose, also known as blood sugar, is the concentration of glucose in the blood. Glucose is a simple sugar that serves as the main source of energy for the body's cells. It is carried to each cell through the bloodstream and is absorbed into the cells with the help of insulin, a hormone produced by the pancreas.
The normal range for blood glucose levels in humans is typically between 70 and 130 milligrams per deciliter (mg/dL) when fasting, and less than 180 mg/dL after meals. Levels that are consistently higher than this may indicate diabetes or other metabolic disorders.
Blood glucose levels can be measured through a variety of methods, including fingerstick blood tests, continuous glucose monitoring systems, and laboratory tests. Regular monitoring of blood glucose levels is important for people with diabetes to help manage their condition and prevent complications.
Phosphoserine is not a medical term per se, but rather a biochemical term. It refers to a post-translationally modified amino acid called serine that has a phosphate group attached to its side chain. This modification plays a crucial role in various cellular processes, including signal transduction and regulation of protein function. In medical contexts, abnormalities in the regulation of phosphorylation (the addition of a phosphate group) and dephosphorylation (the removal of a phosphate group) have been implicated in several diseases, such as cancer and neurological disorders.
A Glucose Tolerance Test (GTT) is a medical test used to diagnose prediabetes, type 2 diabetes, and gestational diabetes. It measures how well your body is able to process glucose, which is a type of sugar.
During the test, you will be asked to fast (not eat or drink anything except water) for at least eight hours before the test. Then, a healthcare professional will take a blood sample to measure your fasting blood sugar level. After that, you will be given a sugary drink containing a specific amount of glucose. Your blood sugar levels will be measured again after two hours and sometimes also after one hour.
The results of the test will indicate how well your body is able to process the glucose and whether you have normal, impaired, or diabetic glucose tolerance. If your blood sugar levels are higher than normal but not high enough to be diagnosed with diabetes, you may have prediabetes, which means that you are at increased risk of developing type 2 diabetes in the future.
It is important to note that a Glucose Tolerance Test should be performed under the supervision of a healthcare professional, as high blood sugar levels can be dangerous if not properly managed.
SRC homology domains, often abbreviated as SH domains, are conserved protein modules that were first identified in the SRC family of non-receptor tyrosine kinases. These domains are involved in various intracellular signaling processes and mediate protein-protein interactions. There are several types of SH domains, including:
1. SH2 domain: This domain is approximately 100 amino acids long and binds to specific phosphotyrosine-containing motifs in other proteins, thereby mediating signal transduction.
2. SH3 domain: This domain is about 60 amino acids long and recognizes proline-rich sequences in target proteins, playing a role in protein-protein interactions and intracellular signaling.
3. SH1 domain: Also known as the tyrosine kinase catalytic domain, this region contains the active site responsible for transferring a phosphate group from ATP to specific tyrosine residues on target proteins.
4. SH4 domain: This domain is present in some SRC family members and serves as a membrane-targeting module by interacting with lipids or transmembrane proteins.
These SH domains allow SRC kinases and other proteins containing them to participate in complex signaling networks that regulate various cellular processes, such as proliferation, differentiation, survival, and migration.
Protein Tyrosine Phosphatase, Non-Receptor Type 11 (PTPN11) is a gene that encodes for the protein tyrosine phosphatase SHP-2. This enzyme regulates various cellular processes, including cell growth, differentiation, and migration, by controlling the balance of phosphorylation and dephosphorylation of proteins involved in signal transduction pathways. Mutations in PTPN11 have been associated with several human diseases, most notably Noonan syndrome and its related disorders, as well as certain types of leukemia.
Insulin receptor substrate
Pleckstrin homology domain
NISCH
WDR6
Protein-protein interaction
OCC-1
SH2B2
SHANK3
BAIAP2
SHANK1
2001 in science
SHANK2
Alexei Kharitonenkov
IRS4
IRS2
Lipolysis
David Gems
Aganirsen
Phosphotyrosine-binding domain
Bcl-2
Janus kinase 2
SHC1
GAPVD1
Parvulin 14
AP3S1
Age-1
Phosphoinositide 3-kinase
GRB2-associated-binding protein 1
IMD domain
ATP2A1
Insulin receptor substrate 1 is a substrate of the Pim protein kinases | Oncotarget
Insulin receptor substrate - Wikipedia
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Human cytomegalovirus attenuates AKT activity by destabilizing insulin receptor substrate proteins | Sciety
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Anti-diabetic activity of chromium picolinate and biotin in rats with type 2 diabetes induced by high-fat diet and...
t(X;7)(q22;q34) IRS4/TRB
Table of Contents - March 09, 2005, 25 (10) | Journal of Neuroscience
The function of GRB2 in linking the insulin receptor to Ras signaling pathways
Frontiers | Bioactivity Screening of Microalgae for Antioxidant, Anti-Inflammatory, Anticancer, Anti-Diabetes, and...
SMART: Schnipsel domain PH
SMART: PH domain annotation
How do tumors grow and spread?
Isolation of Antidiabetic Principle from Fruit Rinds of Punica granatum
IRS1 Monoclonal Antibody (OTI2B10) (TA808550)
Prognosis
Molecules | Free Full-Text | The Potential Mechanisms of Berberine in the Treatment of Nonalcoholic Fatty Liver Disease
Parity-Induced Decrease in Systemic Growth Hormone Alters Mammary Gland Signaling: A Potential Role in Pregnancy Protection...
Interaction between nuclear insulin receptor substrate-2 and NF-κB in IGF-1 induces response in breast cancer cells
Human IRS2 Antibody MAB6347: R&D Systems
3,3′‐Diindolylmethane Enhances Glucose Uptake Through Activation of Insulin Signaling in 3T3‐L1 Adipocytes | Request PDF
JCI - Comments
Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats |...
Drosophila Peptide Hormones Allatostatin A and Diuretic Hormone 31 Exhibiting Complementary Gradient Distribution in Posterior...
Frontiers | Exploration the Mechanism of Doxorubicin-Induced Heart Failure in Rats by Integration of Proteomics and...
Maternal Obesity and Western-Style Diet Impair Fetal and Juvenile Offspring Skeletal Muscle Insulin-Stimulated Glucose...
Alterations in brain glycogen levels influence life-history traits and reduce the lifespan in female Drosophila melanogaster |...
Phosphorylation22
- The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. (oncotarget.com)
- To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. (oncotarget.com)
- This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. (oncotarget.com)
- An insulin-sensitive serine/threonine kinase casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. (thermofisher.com)
- Thus, casein kinase II-catalyzed phosphorylation of IRS-1 may be a component of the intracellular insulin signaling cascade. (thermofisher.com)
- Depending upon the receptor, IRS2 undergoes phosphorylation, either via Tyk2 following type I IFN binding, or via JAK1 and 3 following IL-4, -7 and -15 binding. (rndsystems.com)
- This was associated with DIM‐enhanced phosphorylation of the signaling intermediates Akt, insulin receptor substrate‐1, and insulin receptor early in differentiation. (researchgate.net)
- It is worth noting that we have found the key upstream target of DOX-induced HF, PTP1B, which inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc, and AK4 proteins lead to oxidative stress. (frontiersin.org)
- Maternal WSD reduced insulin-stimulated glucose uptake and impaired insulin signaling at the level of Akt phosphorylation in fetal muscle. (diabetesjournals.org)
- In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and postweaning WSD and corresponded to modest reductions in insulin-stimulated Akt phosphorylation relative to controls. (diabetesjournals.org)
- The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2, Journal of Biological Chemistry (2016). (medicalxpress.com)
- Akt activation leads to the phosphorylation and inactivation of various downstream targets, including glycogen synthase kinase 3 (GSK3), which regulates glycogen synthesis, and the mammalian target of rapamycin (mTOR), which controls protein synthesis and cell growth. (ebiwinner.com)
- On the other hand, interestingly, one of the key downstream insulin signaling molecules, protein kinase-B (PKB, or Akt) and its phosphorylation (pAkt) were significantly increased for cyclically stretched adipocytes relative to unstretched control. (unl.edu)
- Moreover, cyclic stretch upregulated the phosphorylation of 5'-AMP-activated protein kinase (pAMPK). (unl.edu)
- Combined data may suggest that mechanical stretch activates the insulin signaling pathway downstream of IRS-1, and possibly by the phosphorylation of Akt through AMPK activation. (unl.edu)
- Since it is known that adipokines such as leptin and adiponectin can instigate their insulin signaling sensitizing effect via AMPK and Akt, we propose a mechanism that mechanical stretching of adipocytes may induce the secretion of insulin sensitizing adipokines like leptin and/or adiponectin, which in turn activates AMPK and Akt phosphorylation and, ultimately, improves insulin signaling in the adipose tissue. (unl.edu)
- The post receptor pathways that cause the insulin resistance include decreased phosphorylation of insulin receptor, insulin receptor substrate-1 and activation of Akt/PKB. (massgeneral.org)
- In Fao or NIH3T3 cells stably expressing IR, overexpression of PKCζ enhances the dissociation from IR and decrease in IRS1 tyrosine phosphorylation caused by prolonged insulin stimulation (Riu et al. (reactome.org)
- Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). (reactome.org)
- In cultured human aortic endothelial cell (HAEC) models, insulin stimulates an intracellular signalling cascade resulting in activating phosphorylation of Insulin Receptor Substrate-1 (IRS-1), Protein kinase B (PKB. (endocrine-abstracts.org)
- Upon tyrosine phosphorylation, insulin receptor substrate proteins interact with specific SH2 DOMAIN containing proteins that are involved in insulin receptor signaling. (bvsalud.org)
- Further, HMW adiponectin pretreatment decreases glycogen synthase kinase-3ß (GSK-3ß) inactivation by abrogating LPS-induced Akt (Ser473) phosphorylation, which subsequently suppresses LPS-induced CCAAT/enhancer binding protein ß (C/EBPß) protein translation and nuclear translocation. (bvsalud.org)
IRS18
- This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. (oncotarget.com)
- Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1 S1101 and IRS2 S1149 are Pim substrates. (oncotarget.com)
- These results demonstrate that IRS1 S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy. (oncotarget.com)
- IRS1 (see also Insulin receptor substrate 1) IRS2 (see also Insulin receptor substrate 2) IRS3P - a pseudogene IRS4 van der Geer P, Wiley S, Pawson T (1999). (wikipedia.org)
- mTORC1 contributes to insulin resistance by causing proteasomal degradation of insulin receptor substrate (IRS) proteins, such as IRS1, which are necessary for the recruitment of PI3K to growth factor receptors. (sciety.org)
- Human recombinant protein fragment corresponding to amino acids 1-280 of human IRS1 produced in E.coli. (thermofisher.com)
- Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. (jci.org)
- Participants underwent vastus lateralis muscle biopsies before and 30-minutes post exercise to assess phosphorylated focal adhesion kinase (FAK Tyr397 ), insulin receptor substrate 1 ( PanTyr IRS1), and ribosomal protein S6 kinase beta-1 (p70S6K Thr389 ) via ELISA. (wku.edu)
Resistance25
- Deletion of Irsl produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. (silverchair.com)
- In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and β-cell failure. (silverchair.com)
- Metabolic syndrome (syndrome X, insulin resistance) is a multifactorial disease with multiple risk factors that arises from insulin resistance accompanying abnormal adipose deposition and function. (medscape.com)
- Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. (jci.org)
- de la Monte SM, Longato L, Tong M, Wands JR (2009) Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. (springer.com)
- Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. (springer.com)
- Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K (2010) Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. (springer.com)
- Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. (jci.org)
- In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. (jci.org)
- We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. (jci.org)
- In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. (jci.org)
- Insulin resistance is defined as an inadequate response by insulin target tissues, such as skeletal muscle, liver, and adipose tissue, to the physiologic effects of circulating insulin. (jci.org)
- The causes of insulin resistance can be genetic and/or acquired. (jci.org)
- Nonetheless, it is likely that any genetic component must interact with environmental factors in order for insulin resistance to develop into a pathophysiologically meaningful abnormality. (jci.org)
- In the presence of a robust compensatory insulin secretory response to insulin resistance, glucose levels can remain relatively normal. (jci.org)
- Critically ill patients also have insulin resistance, which leads to hyperglycemia, decreased glucose uptake in muscle, enhanced gluconeogenesis and glycogenolysis and decreased protein anabolism. (massgeneral.org)
- Insulin resistance states are associated with endothelial dysfunction, but the molecular mechanisms underlying this association are incompletely understood. (endocrine-abstracts.org)
- Metabolic syndrome is consists of abdominal obesity, hyperglycemia, insulin resistance, hypertriglyceridemia, low HDL cholesterol and hypertension and is an important risk factor for atherosclerotic cardiovascular disease [ 16 ]. (biomedcentral.com)
- Our aim was to evaluate the prevalence of insulin resistance in Egyptian patients with chronic HCV genotype 4 infection, to assess factors associated with insulin resistance and to test the impact of insulin resistance on outcomes of treatment with pegylated interferon/ribavirin. (who.int)
- This study confirms that insulin resistance affects treatment outcome, and thus HOMA-IR testing before initiation of therapy may be a cost-effective tool. (who.int)
- Hypertriglyceridemia is indicative of insulin resistance when present with low high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL), while elevated triglyceride is a clinical risk factor for coronary artery disease (CAD), especially when low HDL is present. (medscape.com)
- Characteristics of insulin resistance in Korean adults from the perspective of circadian and metabolic sensing genes. (cdc.gov)
- 4 infection, to assess factors associated with insulin resistance and to test the impact of insulin resistance on outcomes of treatment with pegylated interferon/ribavirin. (who.int)
- conditions such as insulin resistance in the most prevalent genotype in Egypt patients with HCV infection. (who.int)
- Adding to this grow- genotype 4, to assess factors associated proportion of Egyptians estimated to be ing body of evidence, it is now suggested with insulin resistance in those patients chronically infected was 9.8% ( 1 ). (who.int)
Kinase10
- The phosphoinositide 3-kinase (PI3K)/AKT pathway plays crucial roles in cell viability and protein synthesis and is frequently co-opted by viruses to support their replication. (sciety.org)
- They act as mediators between multiple growth factor receptors that possess tyrosine kinase activity, such as the insulin and insulin growth factor receptors, and a complex network of intracellular signalling molecules, resulting in activation of, for example, the PI3K and RAS/ERK pathways and subsequent transcription of target genes. (atlasgeneticsoncology.org)
- Pleckstrin, the protein where this domain was first detected, is the major substrate of protein kinase C in platelets. (embl.de)
- A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. (jci.org)
- Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. (jci.org)
- Thus, despite the decrease in p85α, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. (jci.org)
- The key components of the Igf 1 receptor signaling pathway include the IGF-1 receptor, insulin receptor substrate proteins (IRS), phosphatidylinositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). (ebiwinner.com)
- One key insight into the Igf 1 receptor signaling pathway is the involvement of phosphoinositide 3-kinase (PI3K) and Akt. (ebiwinner.com)
- This class of drug has been reported to exert PPAR gamma receptor dependent as well as receptor independent effects, possibly via AMP kinase activation (AMPK) but the precise mode of action resulting in improved cardiovascular outcome remains uncertain.We studied the effects of rosigl. (endocrine-abstracts.org)
- A structurally-related group of signaling proteins that are phosphorylated by the INSULIN RECEPTOR PROTEIN-TYROSINE KINASE. (bvsalud.org)
Adaptor Proteins1
- Despite significant homology between IRS-1 and IRS-2, recent studies have revealed distinct functions for these adaptor proteins in regulating breast cancer progression. (spandidos-publications.com)
IRS22
- Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. (nih.gov)
- IRS2 (insulin receptor substrate 2) is a 180-190 kDa substrate intermediate that lies between various cytokine receptors and downstream signaling molecules. (rndsystems.com)
Signalling pathways2
- As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. (silverchair.com)
- Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implicate IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis. (silverchair.com)
Response to insulin1
- In response to insulin stimulation, this complex bound to tyrosine-phosphorylated IRS-1 (insulin receptor substrate-1) and Shc. (nih.gov)
Sensitivity7
- This study aimed to determine whether I3C or DIM could increase glucose uptake via enhanced insulin sensitivity in 3T3‐L1 adipocytes, as well as the mechanism involved. (researchgate.net)
- Conclusions Our findings suggest that DIM may improve insulin sensitivity through the activation of the insulin signaling pathway, leading to enhanced glucose uptake. (researchgate.net)
- DIM, a major metabolite of indole-3-carbinol, which is naturally produced in broccoli and cabbage, enhances glucose uptake through the improvement of insulin sensitivity in 3T3-L1 cells [13] . (researchgate.net)
- Stanhope KL, Schwarz JM, Keim NL et al (2009) Consuming fructose-sweetened, not glucose-sweetened, beverages increase visceral adiposity and lipids and decrease insulin sensitivity in overweight/obese men. (springer.com)
- Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity. (jci.org)
- The hallmarks of impaired insulin sensitivity in these three tissues are decreased insulin-stimulated glucose uptake into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue. (jci.org)
- In this study, with the assumption that adipose tissue can be mechanically responsive (as is the case for well-known musculoskeletal tissues), we hypothesized that mechanical loading applied to the adipose tissue and its component cells, such as adipocytes, may play a role in the exercise control of insulin sensitivity. (unl.edu)
IRSp534
- Insulin receptor substrate protein 53 (IRSp53) as a binding partner of anti-metasatasis molecule NESH, a member of Abelson interactor prote in family. (nii.ac.jp)
- The insulin receptor substrate p53 (IRSp53), an Src homology 3 (SH3) adapter protein and regulator of the actin cytoskeleton, was identified as an espin-binding protein in yeast two-hybrid screens. (northwestern.edu)
- Thus, the PC espins exhibit the properties of modular actin-bundling proteins with the potential to influence the organization and dynamics of the actin cytoskeleton in PC dendritic spines and to participate in multiprotein complexes involving SH3 domain-containing proteins, such as IRSp53. (northwestern.edu)
- The FH1 domain is also a binding site for diverse SH3-domain containing proteins like Src-like non-receptor tyrosine kinases, WISH (WASP-interacting SH3 protein) and IRSp53 (insulin receptor substrate) in mammals, and Hof1p in yeast [ 6 ]. (biomedcentral.com)
Metabolism4
- Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia and alterations in carbohydrate, lipid, and protein metabolism, associated with absolute or relative deficiencies in insulin secretion and/or insulin action [ 1 ]. (hindawi.com)
- The physiological functions of the Igf 1 receptor signaling pathway include regulation of growth and development, metabolism, tissue repair, and immune function. (ebiwinner.com)
- Insulin-like growth factor-1 (IGF-1), a member of a family of growth factors that are structurally closely related to pro-insulin, has shown profound effects on chondrocyte biological behavior and fundamentally regulates cartilage matrix metabolism during cartilage repair. (biomedcentral.com)
- Role of beta-2 adrenergic receptor polymorphism (rs1042714) on body weight and glucose metabolism response to a meal-replacement hypocaloric diet. (cdc.gov)
Polymorphism1
- This study aims to identify insulin receptor substrate 1 (IRS-1) gene polymorphism Gly972Arg as the risk factor for ischemic stroke among Indonesian subjects. (biomedcentral.com)
Hyperglycemia1
- Type 1 diabetes mellitus (insulin-dependent diabetes) is characterized by hyperglycemia caused by an insulin deficiency. (researchgate.net)
Secretion2
- Physical exercise has been demonstrated to positively affect insulin signaling activities potentially through increasing the secretion of insulin sensitizing adipokines and/or decreasing the secretion of pro-inflammatory insulin desensitizing adipokines. (unl.edu)
- However, cellular and molecular level mechanisms governing the exercise control of circulating adipokine secretion and its control of insulin signaling are not known. (unl.edu)
Adipose2
- In addition to serving as energy storage for the body, evidence also suggests that adipose tissue behaves as an endocrine organ capable of secreting bioactive cytokines known as adipokines, which mediate insulin signaling pathways in various tissues. (unl.edu)
- The fusion of insulin-stimulated GLUT4-containing vesicles (GSV) with the plasma membrane (PM) of adipose or skeletal muscle cells is governed by regulated exocytosis. (endocrine-abstracts.org)
Effects of insulin1
- A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. (silverchair.com)
Phosphorylates2
- SIK2 is found in adipocytes and phosphorylates a specific serine residue in insulin receptor substrate-1. (axonmedchem.com)
- Upon activation of the receptor, PI3K is recruited to the receptor complex and phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). (ebiwinner.com)
Pathway23
- The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. (oncotarget.com)
- 3,3′-diindolylmethane (DIM)-a natural compound produced from indole-3-carbinol, found in cruciferous vegetables-enhances glucose uptake by increasing the activation of the insulin signaling pathway in 3T3-L1 adipocytes. (researchgate.net)
- The switch, they say, is composed of regulatory proteins that control an immune signaling pathway in cells. (medicalxpress.com)
- Asthma patients are constantly firing through this pathway because those proteins are stuck in the 'on' position, without proper control by other proteins that shut down this reaction," says Nicola Heller, Ph.D., assistant professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine. (medicalxpress.com)
- The new research , reported Nov. 25 in the Journal of Biological Chemistry , investigated the role of two proteins, GRB10 and p70S6K, in the control of the signaling pathway that activates M2 cells. (medicalxpress.com)
- In their previous work , also published in the Journal of Biological Chemistry Sept. 23, Heller's group found that the inflammatory pathway involving the two proteins begins with interleukin 4 (IL-4), an immune system chemical that passes through a protein named IRS-2 before activating the M2 cells. (medicalxpress.com)
- The IGF-1 receptor signaling pathway plays a crucial role in cell growth, proliferation, and survival. (ebiwinner.com)
- Learn more about the IGF-1 receptor signaling pathway and its potential as a therapeutic target. (ebiwinner.com)
- The Igf 1 receptor signaling pathway is a cellular signaling pathway that is activated by the binding of insulin-like growth factor 1 (IGF-1) to its receptor on the cell surface. (ebiwinner.com)
- What are the key components of the Igf 1 receptor signaling pathway? (ebiwinner.com)
- How does the Igf 1 receptor signaling pathway regulate cell growth and survival? (ebiwinner.com)
- The Igf 1 receptor signaling pathway regulates cell growth and survival by activating downstream signaling molecules that promote cell proliferation, inhibit apoptosis, and stimulate protein synthesis. (ebiwinner.com)
- Dysregulation of the Igf 1 receptor signaling pathway has been implicated in various diseases, including cancer, diabetes, and neurodegenerative disorders. (ebiwinner.com)
- What are the potential therapeutic targets in the Igf 1 receptor signaling pathway? (ebiwinner.com)
- Potential therapeutic targets in the Igf 1 receptor signaling pathway include the IGF-1 receptor itself, as well as downstream signaling molecules such as PI3K, AKT, and mTOR. (ebiwinner.com)
- The Igf 1 receptor signaling pathway is regulated by various mechanisms, including ligand availability, receptor expression and activation, as well as negative feedback loops and cross-talk with other signaling pathways. (ebiwinner.com)
- What are the current research efforts focused on in the field of Igf 1 receptor signaling pathway? (ebiwinner.com)
- Current research efforts in the field of Igf 1 receptor signaling pathway are focused on understanding the molecular mechanisms underlying its regulation, identifying novel therapeutic targets, and developing strategies to modulate its activity for the treatment of various diseases. (ebiwinner.com)
- This pathway is activated by the binding of insulin-like growth factor 1 (IGF-1) to its receptor, leading to the activation of downstream signaling cascades. (ebiwinner.com)
- Understanding the Igf 1 receptor signaling pathway has important implications for various diseases, including cancer. (ebiwinner.com)
- In conclusion, the Igf 1 receptor signaling pathway is a complex and highly regulated pathway that plays a critical role in various biological processes. (ebiwinner.com)
- One recognized pathway for accelerated muscle protein breakdown is the ubiquitin-proteosome pathway. (massgeneral.org)
- The insulin-like growth factor (IGF) signaling pathway has been implicated in articular cartilage repair. (biomedcentral.com)
Adipocytes1
- As a proof-ofconcept test, we applied cyclic stretch loading to the adipocyte model, differentiated adipocytes from 3T3-L1 preadipocytes, and evaluated stretch-induced activation of key insulin signaling molecules. (unl.edu)
Stimulation2
- IRS-1, a major substrate of the insulin receptor, is phosphorylated in response to stimulation of cells by insulin, insulin-like growth factor 1 (IGF-1) and interleukin 4 (IL-4). (thermofisher.com)
- Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. (nih.gov)
Humans3
- Our results establish espin as an essential protein for hearing and vestibular function in humans. (bmj.com)
- The lab has used conditional knockouts to complement in vitro models using primary islets from humans/rodents to dissect cross-talk between insulin/IGF-I, glucose, and incretin (glucagon like-peptide-1) signaling pathways in islet cells. (joslin.org)
- In humans, low protein intake by women in late but intrauterine exposure was (20). (cdc.gov)
Molecules2
- Our studies have demonstrated apoptosis in muscles following critical illness and/or immobilization alone, with upregulation of certain death-inducing molecules and downregulation of some anti-apoptotic genes and/or their proteins. (massgeneral.org)
- Sometimes various globular proteins embedded in the matrix function as receptors and help transport molecules across the membrane. (msdmanuals.com)
Kinases4
- Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. (oncotarget.com)
- Insulin-induced activation of extracellular signal-regulated kinases [ERKs, also known as mitogen-activated protein (MAP) kinases] is mediated by Ras. (nih.gov)
- Ser/Thr protein kinases such as the Akt/Rac family, the beta-adrenergic receptor kinases, the mu isoform of PKC and the trypanosomal NrkA family. (embl.de)
- Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily. (embl.de)
Activation of the insulin1
- In contrast to the activated epidermal growth factor receptor that binds the GRB2-Sos complex directly, activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptor to Ras signaling pathways. (nih.gov)
Homology4
- Here, we show that insulin-induced activation of ERKs was enhanced by stable overexpression of growth factor receptor-bound protein 2 (GRB2) but not by overexpression of GRB2 proteins with point mutations in the Src homology 2 and 3 domains. (nih.gov)
- Pleckstrin homology (PH) domains are small modular domains that occur in a large variety of proteins. (embl.de)
- Formins are multidomain proteins defined by a conserved FH2 (formin homology 2) domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1) domain. (biomedcentral.com)
- The proteins share an N-terminal PLECKSTRIN HOMOLOGY DOMAIN, a phosphotyrosine-binding domain that interacts with the phosphorylated INSULIN RECEPTOR, and a C-terminal TYROSINE-rich domain. (bvsalud.org)
Binds2
- Thus, the insulin receptor binds IRS. (wikipedia.org)
- Mouse protein citron, a putative rho/rac effector that binds to the GTP-bound forms of rho and rac. (embl.de)
Phosphotyrosine bindin1
- IRS-1, for example, is an IRS protein that contains a phosphotyrosine binding-domain (PTB-domain). (wikipedia.org)
Gene4
- RQ-PCR and Western blot analysis confirmed overexpression of IRS4 at the gene and protein level. (atlasgeneticsoncology.org)
- The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus. (atlasgeneticsoncology.org)
- Description of the protein which includes the UniProt Function and the NCBI Gene Summary. (nih.gov)
- Moreover, phosphodiesterase 4D (PDE4D) [ 13 ], and 5-lipoxygenase gene activating protein (ALOX5AP) [ 14 ], were shown to be significantly related with ischemic stroke due to progressive changes in the walls of blood vessels resulting in the increased atherosclerosis process. (biomedcentral.com)
Hypertriglyceridemia1
- In conclusion, cognitive deficits induced by chronic liquid fructose consumption are not exclusively related to increased caloric intake and are correlated with hypertriglyceridemia, impaired insulin signaling, increased oxidative stress and altered mitochondrial dynamics, especially in the frontal cortex. (springer.com)
Regulate3
- We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts. (nih.gov)
- These results indicate that the two intestinal secretory peptides antagonistically regulate adult lifespan and intestinal senescence through multiple pathways, irrespective of insulin, which implicates a complementary gradient distribution of each of the hormone-producing EEs, consistent with local requirements for cell activity along the posterior midgut. (bioone.org)
- We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. (jci.org)
ABSTRACT1
- abstract = "We identified a group of actin-binding-bundling proteins that are expressed in cerebellar Purkinje cells (PCs) but are not detected in other neurons of the CNS. (northwestern.edu)
Impairs1
- We used a Japanese macaque model to investigate whether maternal obesity combined with a Western-style diet (WSD) impairs offspring muscle insulin action. (diabetesjournals.org)
Isoforms1
- These proteins are novel isoforms of the actin-bundling protein espin that arise through the use of a unique site for transcriptional initiation and differential splicing. (northwestern.edu)
Genetic2
- First, the lab is investigating the significance of growth factor signaling mechanisms in the regulation of islet biology by creating genetic models to examine the roles of insulin/IGF-1 receptors and their substrate proteins. (joslin.org)
- Magnesium Status, Genetic Variants of Magnesium-Related Ion Channel Transient Receptor Potential Membrane Melastatin 6 (TRPM6) and the Risk of Gestational Diabetes Mellitus in Chinese Pregnant Women: A Nested Case-Control Study. (cdc.gov)
Diabetes4
- Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. (nih.gov)
- Previous studies have found that DIM can improve type 2 diabetes by enhancing glucose uptake through the activation of insulin signaling in 3T3-L1 cells, and by lowering the plasma glucose levels in high-fat-diet-fed obese mice [13, 14]. (researchgate.net)
- In this study, we investigated whether DIM could improve insulin-dependent diabetes and nephropathy in streptozotocin (STZ)-induced diabetic mice. (researchgate.net)
- In a cross-sectional study of 48 AD patients without diabetes, 20 cognitively normal diabetic patients, 16 patients with frontotemporal dementia, and 84 cognitively normal controls, researchers found that dysfunctionally phosphorylated insulin receptor substrate-1 (IRS-1), a neuronal protein, is detectable in blood using exosome-based technology and may be able to predict AD up to 10 years before the appearance of symptoms. (medscape.com)
Downstream1
- The researchers saw that decreased GRB10 and p70S6K activity resulted in more of the "on" form of IRS-2, meaning these proteins are responsible for turning off IRS-2 and thereby downstream M2 production. (medicalxpress.com)
Ligand1
- Insulin receptor substrate (IRS) is an important ligand in the insulin response of human cells. (wikipedia.org)
Domain-containi1
- PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. (nih.gov)
Pancreatic1
- This was the first study to suggest that smoking tension and vascular defects (8,9), altered fetal pancreatic during pregnancy is linked to adverse changes in the lipo- development and structure (10), altered glucose tolerance protein levels of children (19). (cdc.gov)
Synthesis1
- Therefore, the anabolic actions of insulin, including glucose uptake and protein synthesis are impaired in critical illness of burns. (massgeneral.org)
Actin-bundlin1
- This phenotype co-segregates with either of two frameshift mutations, 1988delAGAG and 2469delGTCA, in ESPN , which encodes a calcium-insensitive actin-bundling protein called espin. (bmj.com)
Enhance insulin1
- Studies are ongoing on methods to enhance insulin signaling. (massgeneral.org)
Regulatory proteins3
- To achieve this ordering, many cell cycle-regulatory proteins are expressed exclusively when their functions are needed. (umassmed.edu)
- The Benanti lab is interested in understanding why cyclical expression of key regulatory proteins is important for maintaining a stable genome. (umassmed.edu)
- The activity of two regulatory proteins , GRB10 and p70S6K, increased after IL-4 exposure compared to the same cells that were not exposed to IL-4. (medicalxpress.com)
Obesity1
- glucocorticoids, protein restrictions, and maternal diet and obesity. (cdc.gov)
Regulation3
- Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2, BEM3, BUD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1). (embl.de)
- In addition, they are investigating how cell cycle-regulation of chromatin proteins helps to coordinate the condensation of chromosomes with their segregation during mitosis. (umassmed.edu)
- However, gut senescence does not appear to be the direct cause for longevity regulation, as knockdown of both hormone receptors did not affect adult lifespan. (bioone.org)
Expression3
- Plasma parameters and protein/mRNA expression in the frontal cortex and hippocampus were determined. (springer.com)
- Fructose supplementation reduced the expression of antioxidant enzymes and altered the amount of proteins involved in mitochondrial fusion/fission in the frontal cortex. (springer.com)
- Out of 29 liver tissue sections examined, 14 had a low level of expression of insulin receptor type 1 by immunohistochemical studies. (who.int)
Interaction1
- IRS-1 contains three putative binding sites for 14-3-3 (Ser 270, Ser 374 and Ser 641) and the motif around Ser 270 is located in the phosphortyrosine binding domain of IRS-1, which is responsible for the interaction with the insulin receptor. (thermofisher.com)
Roles1
- Conventional murine knockout strategies have started to reveal distinct physiological roles for the IRS proteins. (silverchair.com)