Specific enzyme subunits that form the active sites of the type I and type II cyclic-AMP protein kinases. Each molecule of enzyme contains two catalytic subunits.
An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.
A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.
An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.
A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277)
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
Agents that inhibit PROTEIN KINASES.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
A monomeric calcium-calmodulin-dependent protein kinase subtype that is expressed in a broad variety of mammalian cell types. Its expression is regulated by the action of CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE. Several isoforms of this enzyme subtype are encoded by distinct genes.
A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.
Single chains of amino acids that are the units of multimeric PROTEINS. Multimeric proteins can be composed of identical or non-identical subunits. One or more monomeric subunits may compose a protomer which itself is a subunit structure of a larger assembly.
The rate dynamics in chemical or physical systems.
Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.
The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.
A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.
Established cell cultures that have the potential to propagate indefinitely.
Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.
A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)
A superfamily of PROTEIN-SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
A species of ciliate protozoa. It is used in biomedical research.
An intracellular signaling system involving the MAP kinase cascades (three-membered protein kinase cascades). Various upstream activators, which act in response to extracellular stimuli, trigger the cascades by activating the first member of a cascade, MAP KINASE KINASE KINASES; (MAPKKKs). Activated MAPKKKs phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES which in turn phosphorylate the MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs). The MAPKs then act on various downstream targets to affect gene expression. In mammals, there are several distinct MAP kinase pathways including the ERK (extracellular signal-regulated kinase) pathway, the SAPK/JNK (stress-activated protein kinase/c-jun kinase) pathway, and the p38 kinase pathway. There is some sharing of components among the pathways depending on which stimulus originates activation of the cascade.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
A cyclic AMP-dependent protein kinase subtype primarily found in particulate subcellular fractions. They are tetrameric proteins that contain two catalytic subunits and two type II-specific regulatory subunits.
A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.
A ubiquitous casein kinase that is comprised of two distinct catalytic subunits and dimeric regulatory subunit. Casein kinase II has been shown to phosphorylate a large number of substrates, many of which are proteins involved in the regulation of gene expression.
Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)
The parts of a macromolecule that directly participate in its specific combination with another molecule.
A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA.
A cytoplasmic serine threonine kinase involved in regulating CELL DIFFERENTIATION and CELLULAR PROLIFERATION. Overexpression of this enzyme has been shown to promote PHOSPHORYLATION of BCL-2 PROTO-ONCOGENE PROTEINS and chemoresistance in human acute leukemia cells.
Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.
A proline-directed serine/threonine protein kinase which mediates signal transduction from the cell surface to the nucleus. Activation of the enzyme by phosphorylation leads to its translocation into the nucleus where it acts upon specific transcription factors. p40 MAPK and p41 MAPK are isoforms.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.
Compounds and molecular complexes that consist of very large numbers of atoms and are generally over 500 kDa in size. In biological systems macromolecular substances usually can be visualized using ELECTRON MICROSCOPY and are distinguished from ORGANELLES by the lack of a membrane structure.
A type I cAMP-dependent protein kinase regulatory subunit that plays a role in confering CYCLIC AMP activation of protein kinase activity. It has a lower affinity for cAMP than the CYCLIC-AMP-DEPENDENT PROTEIN KINASE RIBETA SUBUNIT.
An aspect of protein kinase (EC 2.7.1.37) in which serine residues in protamines and histones are phosphorylated in the presence of ATP.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.
Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.
Proteins prepared by recombinant DNA technology.
A 44-kDa extracellular signal-regulated MAP kinase that may play a role the initiation and regulation of MEIOSIS; MITOSIS; and postmitotic functions in differentiated cells. It phosphorylates a number of TRANSCRIPTION FACTORS; and MICROTUBULE-ASSOCIATED PROTEINS.
Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.
The sum of the weight of all the atoms in a molecule.
A ubiquitously expressed protein kinase that is involved in a variety of cellular SIGNAL PATHWAYS. Its activity is regulated by a variety of signaling protein tyrosine kinase.
Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
A cyclic nucleotide derivative that mimics the action of endogenous CYCLIC AMP and is capable of permeating the cell membrane. It has vasodilator properties and is used as a cardiac stimulant. (From Merck Index, 11th ed)
Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS.
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)
A subgroup of mitogen-activated protein kinases that activate TRANSCRIPTION FACTOR AP-1 via the phosphorylation of C-JUN PROTEINS. They are components of intracellular signaling pathways that regulate CELL PROLIFERATION; APOPTOSIS; and CELL DIFFERENTIATION.
N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)-L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor.
The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.
A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.
A cyclic GMP-dependent protein kinase subtype that is expressed in SMOOTH MUSCLE tissues and plays a role in regulation of smooth muscle contraction. Two isoforms, PKGIalpha and PKGIbeta, of the type I protein kinase exist due to alternative splicing of its mRNA.
A specific protein kinase C inhibitor, which inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol.
A long-acting derivative of cyclic AMP. It is an activator of cyclic AMP-dependent protein kinase, but resistant to degradation by cyclic AMP phosphodiesterase.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.
Cell surface proteins that bind cyclic AMP with high affinity and trigger intracellular changes which influence the behavior of cells. The best characterized cyclic AMP receptors are those of the slime mold Dictyostelium discoideum. The transcription regulator CYCLIC AMP RECEPTOR PROTEIN of prokaryotes is not included nor are the eukaryotic cytoplasmic cyclic AMP receptor proteins which are the regulatory subunits of CYCLIC AMP-DEPENDENT PROTEIN KINASES.
A eukayrotic protein serine-threonine phosphatase subtype that dephosphorylates a wide variety of cellular proteins. The enzyme is comprised of a catalytic subunit and regulatory subunit. Several isoforms of the protein phosphatase catalytic subunit exist due to the presence of multiple genes and the alternative splicing of their mRNAs. A large number of proteins have been shown to act as regulatory subunits for this enzyme. Many of the regulatory subunits have additional cellular functions.
Transport proteins that carry specific substances in the blood or across cell membranes.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.

Protein kinase A translocation and insulin secretion in pancreatic beta-cells: studies with adenylate cyclase toxin from Bordetella pertussis. (1/64)

Activation of protein kinase A (cAMP-dependent protein kinase; PKA) triggers insulin secretion in the beta-cell. Adenylate cyclase toxin (ACT), a bacterial exotoxin with adenylate cyclase activity, and forskolin, an activator of adenylate cyclase, both dose-dependently increased insulin secretion in the presence, but not the absence, of glucose in insulin-secreting betaTC3 cells. The stimulation of cAMP release by either agent was dose-dependent but glucose-independent. Omission of extracellular Ca(2+) totally abolished the effects of ACT on insulin secretion and cytosolic cAMP accumulation. ACT and forskolin caused rapid and dramatic increases in cytosolic Ca(2+), which were blocked by nifedipine and the omission of extracellular Ca(2+). Omission of glucose completely blocked the effects of forskolin and partially blocked the effects of ACT on cytosolic Ca(2+). PKA alpha, beta and gamma catalytic subunits (Calpha, Cbeta and Cgamma respectively) were identified in betaTC6 cells by confocal microscopy. Glucose and glucagon-like polypeptide-1 (GLP-1) caused translocation of Calpha to the nucleus and of Cbeta to the plasma membrane and the nucleus, but did not affect the distribution of Cgamma. In conclusion, glucose and GLP-1 amplify insulin secretion via cAMP production and PKAbeta activation.  (+info)

c-MYC activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cbeta) gene. (2/64)

The c-MYC proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and differentiation and broadly implicated in tumorigenesis. Understanding the function of c-MYC and its role in cancer depends upon the identification of c-MYC target genes. Here we show that c-MYC induces the activity of Protein Kinase A (PKA), a key effector of cAMP-mediated signal transduction, by inducing the transcription of the gene encoding the PKA catalytic subunit beta (PKA-Cbeta). c-MYC-mediated induction of PKA-Cbeta gene transcription occurs in multiple tissues, is independent of cell proliferation and is mediated by direct binding of c-MYC to the PKA-Cbeta gene promoter sequences. Constitutive expression of PKA-Cbeta in Rat1A cells induces their transformation, and c-MYC-induced transformation can be reverted by pharmacological inhibition of PKA, suggesting that up-regulation of PKA is critical for c-MYC-associated tumorigenesis. These results indicate that, by activating PKA, c-MYC can provide endogenous activation of the cAMP signal transduction pathway independently of extracellular signals.  (+info)

Loss of protein kinase Calpha expression may enhance the tumorigenic potential of Gli1 in basal cell carcinoma. (3/64)

Activation of the Sonic hedgehog signaling pathway, primarily through mutational inactivation of the PTCH1 gene, is associated with the development of basal cell carcinoma (BCC). Gli1, a member of the Gli family of transcription factors, is expressed in BCC and in transgenic mice targeted expression of Gli1 in basal keratinocytes leads to BCC development. In addition to BCC, previous studies have shown that Gli1 is expressed in the outer root sheath (ORS) of the hair follicle but is absent in interfollicular epidermis. In this study, we have characterized the expression pattern of two protein kinase C (PKC) isoforms expressed in BCC and hair follicles. We have then used reporter assays to investigate the effects of these isoforms on Gli1 transcriptional activity. We report that in BCC sections, PKCalpha but not PKCdelta was weakly expressed in the epidermis, whereas in the hair follicle, PKCalpha was expressed in the ORS and PKCdelta in the inner root sheath. In contrast, neither PKCalpha nor PKCdelta was expressed in BCC tumor islands, although both isoforms were often expressed in the surrounding stroma. In mammalian 293T cells, coexpression of constitutively active PKCalpha reduced the activity of Gli1 in a dose-dependent manner, whereas constitutively active PKCdelta increased the activity of Gli1, although this required higher expression levels. Regulation of mutant Gli1 protein localized exclusively to the nucleus was similar to that of the wild-type protein, indicating that nuclear-cytoplasmic shuttling is not a determinant of Gli1 control by either PKC isoform. Furthermore, PKC regulation of Gli1 did not involve activation of mitogen-activated protein kinase signaling. Finally, we show that exogenous Gli1 does not alter the expression of PKCalpha in human primary keratinocytes, suggesting that loss of this isoform in BCC is not via Hedgehog signaling. As BCCs have been proposed to originate from the ORS, loss of PKCalpha expression may be relevant to tumor formation; this may, in part, be because of the predicted increase in Gli1 transcriptional activity.  (+info)

Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers. (4/64)

The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to delta-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA C alpha translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-beta gamma dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by beta gamma dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.  (+info)

Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization. (5/64)

Mutations in the NF2 tumor suppressor gene encoding merlin induce the development of tumors of the nervous system. Merlin is highly homologous to the ERM (ezrin-radixin-moesin) family of membrane/cytoskeleton linker proteins. However, the mechanism for the tumor suppressing activity of merlin is not well understood. Previously, we characterized a novel role for merlin as a protein kinase A (PKA)-anchoring protein, which links merlin to the cAMP/PKA signaling pathway. In this study we show that merlin is also a target for PKA-induced phosphorylation. In vitro [gamma-(33)P]ATP labeling revealed that both the merlin N and C termini are phosphorylated by PKA. Furthermore, both in vitro and in vivo phosphorylation studies of the wild-type and mutated C termini demonstrated that PKA can phosphorylate merlin at serine 518, a site that is phosphorylated also by p21-activated kinases (PAKs). Merlin was phosphorylated by PKA in cells in which PAK activity was suppressed, indicating that the two kinases function independently. Both in vitro and in vivo interaction studies indicated that phosphorylation of serine 518 promotes heterodimerization between merlin and ezrin, an event suggested to convert merlin from a growth-suppressive to a growth-permissive state. This study provides further evidence on the connection between merlin and cAMP/PKA signaling and suggests a role for merlin in the cAMP/PKA transduction pathway.  (+info)

Sperm-specific protein kinase A catalytic subunit Calpha2 orchestrates cAMP signaling for male fertility. (6/64)

An unusual cAMP signaling system mediates many of the events that prepare spermatozoa to meet the egg. Its components include the atypical, bicarbonate-stimulated, sperm adenylyl cyclase and a cAMP-dependent protein kinase (PKA) with the unique catalytic subunit termed Calpha(2) or C(s). We generated mice that lack Calpha(2) to determine its importance in the events downstream of cAMP production. Male Calpha(2) null mice produce normal numbers of sperm that swim spontaneously in vitro. Thus, Calpha(2) has no required role in formation of a functional flagellum or the initiation of motility. In contrast, we find that Calpha(2) is required for bicarbonate to speed the flagellar beat and facilitate Ca(2+) entry channels. In addition, Calpha(2) is needed for the protein tyrosine phosphorylation that occurs late in the sequence of sperm maturation and for a negative feedback control of cAMP production, revealed here. Consistent with these specific defects in several important sperm functions, Calpha(2) null males are infertile despite normal mating behavior. These results define several crucial roles of PKA in sperm cell biology, bringing together both known and unique PKA-mediated events that are necessary for male fertility.  (+info)

Changes in cAMP-dependent protein kinase (PKA) and progesterone secretion in luteinizing human granulosa cells. (7/64)

Luteinization of follicular granulosa cells leads to an increase in progesterone secretion that is regulated by luteinizing hormone (LH). LH acts mainly by elevating intracellular cyclic 3',5'-adenosine monophosphate (cAMP) and activating cAMP-dependent protein kinase (PKA). In this study, we have examined the role of PKA in relation to progesterone output by luteinizing human granulosa cells. Human granulosa cells were obtained by percoll gradient centrifugation of follicular aspirates of patients undergoing oocyte retrieval for assisted conception. Cells were cultured in serum-supplemented medium for up to 3 days in the presence and/or absence of human (h)LH and other cAMP-elevating agents. Spent medium was assayed for cAMP and progesterone content by specific RIA. Cell lysates were collected and assessed for PKA regulatory (R)IIalpha/catalytic (C)alpha expression by Western blotting. Although basal progesterone secretion increased progressively throughout culture, cAMP levels remained unchanged. Under basal conditions, PKA RIIalpha/Calpha expression appeared to increase throughout the 3-day culture period. In the presence of hLH and other cAMP-elevating agents, progesterone secretion increased in a dose-dependent manner coincident with an increase in cAMP. However, despite the increase in both progesterone secretion and cAMP accumulation, there was a dose-dependent decrease in both PKA RIIalpha and Calpha expression. Thus, data presented in this study show that increases in progesterone secretion in luteinizing human granulosa cells can be dissociated from increases in PKA expression. This notion implies that progesterone secretion may be regulated by PKA-dependent as well as PKA-independent mechanisms.  (+info)

Stress stimulates AMP-activated protein kinase and meiotic resumption in mouse oocytes. (8/64)

This study examined the effects of three different cellular stresses on oocyte maturation in meiotically arrested mouse oocytes. Cumulus-cell enclosed oocytes (CEO) or denuded oocytes (DO) from immature, eCG-primed mice were cultured for 17-18 h in dbcAMP-containing medium plus increasing concentrations of the metabolic poison, sodium arsenite, or the free radical-generating agent, menadione. Alternatively, oocytes were exposed to osmotic stress by pulsing with sorbitol and returned to control inhibitory conditions for the duration of culture. Arsenite and menadione each dose-dependently induced germinal vesicle breakdown (GVB) in both DO and CEO. DO, but not CEO, pulsed for 60 min with 500 mM sorbitol were stimulated to resume maturation. The lack of effect in CEO suggests that the cumulus cells may be playing a protective role in osmotic stress-induced GVB. The AMP-activated protein kinase (PRKA; formerly known as AMPK) inhibitors, compound C and araA, completely blocked the meiosis-stimulating effects of all the tested stresses. Western blots showed that acetyl-CoA carboxylase, an important substrate of PRKA, was phosphorylated before GVB, supporting a role for PRKA in stress-induced maturation. Together, these data show that a variety of stresses stimulate GVB in meiotically arrested mouse oocytes in vitro and suggest that this effect is mediated through activation of PRKA.  (+info)

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development.. METHODS: We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other ...
PRKACA - PRKACA (untagged)-Human protein kinase, cAMP-dependent, catalytic, alpha (PRKACA), transcript variant 1 available for purchase from OriGene - Your Gene Company.
PRKACA Human Recombinant produced in Sf9 Baculovirus cells is a single, glycosylated polypeptide chain containing 578 amino acids.
PRKACB - Lenti ORF clone of Human protein kinase, cAMP-dependent, catalytic, beta (PRKACB), transcript variant 3 , Myc-DDK-tagged available for purchase from OriGene - Your Gene Company.
Wiki-Pi: a web resource for human protein-protein interactions. It shows genes and PPIs with information about pathways, protein-protein interactions (PPIs), Gene Ontology (GO) annotations including cellular localization, molecular function and biological process, drugs, diseases, genome-wide association studies (GWAS), GO enrichments, PDB ID, Uniprot ID, HPRD ID, and word cloud from pubmed abstracts.
Wiki-Pi: a web resource for human protein-protein interactions. It shows genes and PPIs with information about pathways, protein-protein interactions (PPIs), Gene Ontology (GO) annotations including cellular localization, molecular function and biological process, drugs, diseases, genome-wide association studies (GWAS), GO enrichments, PDB ID, Uniprot ID, HPRD ID, and word cloud from pubmed abstracts.
DLX3 is a novel target of PRKACA, and PRKACA mediates BMP signaling during osteoblast differentiation, at least in part, by phosphorylating DLX3 and modulating the protein stability and function of DLX3 ...
Homo sapiens protein kinase, cAMP-dependent, catalytic, beta (PRKACB), transcript variant 3, mRNA. (H00005567-R05) - Products - Abnova
KAPCA_HUMAN] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and ...
O95819 (MAP4K4) , Q5VT25 (CDC42BPA) , P41279 (MAP3K8) , Q04759 (PRKCQ) , O75116 (ROCK2) , Q13464 (ROCK1) , Q5S007 (LRRK2) , P25098 (GRK2) , P17612 (PRKACA) , Q9Y5S2 (CDC42BPB) , O94804 (STK10 ...
DGIdb, The Drug Gene Interaction Database, is a research resource that can be used to search candidate genes or drugs against the known and potentially druggable genome.
Mouse polyclonal antibody raised against a partial recombinant RAPGEF3. RAPGEF3 (AAH17728, 772 a.a. ~ 881 a.a) partial recombinant protein with GST tag. (H00010411-A01) - Products - Abnova
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ∼400-kilobase deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis ...
The Khoikhoi people who lived in the Cape Peninsula when the Dutch began trading with the area during the mid 17th century, had a hunting dog which was described as ugly, but noted for its ferocity when acting as a guard dog. This dog measured approximately 18 inches (46 cm) at the withers, with a lean but muscular frame. The ears have been described both as erect and hanging, but the most distinctive feature was the length of hair often growing in the reverse direction along its back. Within 53 years of Dutch colonisation in Southern Africa and the origins of the wagon-trekking boers later known as Afrikaners, who converted vast stretches of wild veld into farmland, hunted for meat and defended their cattle herds, staff, and homesteads from lion, the Europeans were using these local dogs themselves.[3]. By the 1860s, European colonisers had also imported a variety of mainly European dog breeds to this area of Africa, including such dedicated hunting dogs as Great Danes, Bloodhounds, Greyhounds, ...
Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different
Capacitation encompasses the molecular changes sperm undergo to fertilize an oocyte, some of which are postulated to occur via a cAMP-PRKACA (protein kinase A)-mediated pathway. Due to the recent discovery of cAMP-activated guanine nucleotide exchange factors RAPGEF3 and RAPGEF4, we sought to investigate the separate roles of PRKACA and RAPGEF3/RAPGEF4 in modulating capacitation and acrosomal exocytosis. Indirect immunofluorescence localized RAPGEF3 to the acrosome and subacrosomal ring and RAPGEF4 to the midpiece in equine sperm. Addition of the RAPGEF3/RAPGEF4-specific cAMP analogue 8-(p-chlorophenylthio)-2-O-methyladenosine-3,5-cyclic monophosphate (8pCPT) to sperm incubated under both noncapacitating and capacitating conditions had no effect on protein tyrosine phosphorylation, thus supporting a PRKACA-mediated event. Conversely, activation of RAPGEF3/RAPGEF4 with 8pCPT induced acrosomal exocytosis in capacitated equine sperm at rates (34%) similar (P > 0.05) to those obtained in ...
RgdA of A. fumigatus is a homolog of the Mbp1 protein of the budding yeast S. cerevisiae, a putative APSES TF. APSES TFs function as key regulators of fungal morphogenesis and development present in Aspergillus genomes, but only the stuA gene has been studied in A. fumigatus (10, 12, 14, 15, 17). The deletion of rgsA resulted in decreased mycelial growth and conidiation and reduced mRNA levels of key asexual development regulators compared to WT (Fig. 2). The mRNA levels of PKA signaling components were higher in the ΔrgdA strain than in WΤ and complemented strains. Furthermore, the ΔrgdA strain showed higher PKA activity in the absence of cAMP (Fig. 3), suggesting the presence of free PKA catalytic subunits in the cytoplasm (18). Based on these observations, we can propose that RgdA of A. fumigatus is necessary for normal growth and proper asexual development, which may involve regulation of the cAMP-PKA signaling pathway.. The Dpr proteins are known to be activated by the stress-activated ...
Expression of RAPGEF3 (bcm910, cAMP-GEFI, EPAC) in cancer tissue. The cancer tissue page shows antibody staining of the protein in 20 different cancers.
Expression of RAPGEF3 (bcm910, cAMP-GEFI, EPAC) in breast tissue. Antibody staining with HPA040365, HPA043518 and CAB004386 in immunohistochemistry.
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Complete information for RAPGEF3 gene (Protein Coding), Rap Guanine Nucleotide Exchange Factor 3, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Fibrolamellar hepatocellular carcinoma (FHCC) is a rare form of hepatocellular carcinoma (HCC) that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumour cells. Approximately 200 new cases are diagnosed worldwide each year. A recent study showed the presence of the DNAJB1-PRKACA chimeric transcript (resulting from a 400kb somatic deletion on chromosome 19) in 100% of the FHCCs examined (15/15) This gene fusion has been confirmed in a second study. The histopathology of FHCC is characterized by laminated fibrous layers, interspersed between the tumor cells. Cytologically, the tumor cells have a low nuclear to cytoplasmic ratio with abundant eosinophilic cytoplasm. Tumors are non-encapsulated, but well circumscribed, when compared to conventional HCC (which typically has an invasive border). Due to lack of symptoms, until the tumor is sizable, this form of cancer is often advanced when diagnosed. Symptoms include ...
PHACE association is a rare neurocutaneous condition in which facial hemangiomas associate with a spectrum of posterior fossa malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, and eye anomalies. We reported a case of PHACE
cansSAR 3D Structure of 5N3F | CAMP-DEPENDENT PROTEIN KINASE A FROM CRICETULUS GRISEUS IN COMPLEX WITH FRAGMENT LIKE MOLECULE N-[3-(AMINOMETHYL)PHENYL]ACETAMIDE | 5N3F_A | cAMP-dependent protein kinase catalytic subunit alpha - Also known as KAPCA_CRIGR, PRKACA. Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B
Lockheed Martin unveiled the HULC system at the Association of the United States Army Winter Symposium held in Fort Lauderdale, Florida, in February 2009.. In July 2010, the company signed a $1.1m contract with the US Army Natick Soldier Center for testing and evaluating the ruggedised HULC design.. Under the contract, the Natick Soldier Center tested the HULC for its effect on the soldiers performance, the energy that a soldier spends while using it and the adaptability of the system while carrying various loads and moving at various speeds. The contract has also provided provision for field trials of the system.. The HULC underwent laboratory testing in October 2010, after Lockheed Martin upgraded the ruggedised system for flexibility and suitability to a variety of users. The system was put through biomechanical, dynamic load and environmental testing.. Treadmill testing measured the decrease in metabolic cost of the user. The systems sustainability in various environmental conditions was ...
The adoptive parents may be acquainted with to these problems, but in other situations wee if any story may be available. N L H Genes 50 10 10 KREMEN2, ST8SIA1, TNFSF10, ATF6 150 30 30 HADHB, BAX, MAPK13, CYP1A1, ATF2 250 49 51 NFKBIA, PLCB1, ITGB1, MYC, KRAS 350 69 71 PRKACB, FOS, PRKACG, FASN, NFKB1 450 85 95 RAC1, MAP2K2, JUN, TP53, RELA 551 100 119 RAF1, GRB2, PIK3CA, RPS27A, MAPK8 647 117 145 HRAS, MAP2K1, AKT1, RAF1, GRB2 765 125 185 MAPK3, MAPK1, HRAS, MAP2K1, AKT1 Provisions 7. Pregnancy and Yeast InfectionThe Main Benefits: 1 cheap kamagra effervescent 100mg fast delivery erectile dysfunction injections videos. At hand drowning is described as an fact in which a offspring has suffered a submersion injury and has survived for at least 24 hours. It involves removing the little one from the fine kettle of fish area and placing him or her in a dispassionate, nonthreatening, safe square footage where no interaction occurs between the daughter and parents or others exchange for a specifically ...
Highly up-regulated in liver cancer (HULC) was originally identified as the most overexpressed long non-coding RNA in hepatocellular carcinoma. Since its discovery, the aberrant up-regulation of HULC has been demonstrated in other cancer types, including gastric cancer, pancreatic cancer, osteosarcoma and hepatic metastasis of colorectal cancer. Recent discoveries have also shed new light on the upstream molecular mechanisms underlying HULC .... Read More » ...
According to Berkeley Bionics and Lockheed Martin, the HULC biomechanical combat exoskeleton system enables a soldier between 5′ 4″ and 6′ 2″ to carry loads of up to 200 pounds (200 lbs) on the front or back for extended periods of times over any and all terrains by transfering the load weight and soldiers weight to the ground. The load-carrying augmentation/enhancement ability aspect will continue to work when battery power isnt available. The HULC also allows a soldier to run 7 mph for long periods or 10 mph in short bursts. It provides the soldier with full range of motion and, according to the developers, doesnt hinder or impede the warfighters movement in any way/aspect, so he/she can still jump, squat, kneel, crawl, go prone (for survival and stabilized or long-range shooting), etc., and then get right back up.. One of Defense Reviews immediate and primary concerns is whether or not the HULC combat exoskeleton allows the same level of mobility and dexterity required for ...
reference: ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail., Bertran MT, Mouilleron S, Zhou Y, Bajaj R, Uliana F, Kumar GS, van Drogen A, Lee R, Banerjee JJ, Hauri S, OReilly N, Gstaiger M, Page R, Peti W, Tapon N, Nat Commun. 2019 Feb 15;10(1):771. doi: 10.1038/s41467-019-08686-0. PMID: 30770806 ...
မန္မာႏိုင္ငံမွာေတာ့ ေ၀လငါးဖမ္းလုပ္ငန္းကို လုပ္ကိုင္တဲ့လူမရွိေသးဘူးလို႕ ထင္ပါတယ္။ ျမန္မာ့ပင္လယ္ျပင္မွာ ေ၀လငါးဟာ အင္မတန္ေတြ႕ရခဲတာေၾကာင့္ရယ္၊ ေတြ႕ရင္ေတာင္မွ အရြယ္အစားၾကီးမားလြန္းတာရယ္နဲ႕ ေရာင္းခ်မယ့္ေစ်းကြက္မရွိတာရယ္ေၾကာင့္ ဖမ္းဆီးမယ့္လူမရွိပါဘူး။ ေနာက္တစ္ခ်က္ လင္းပိုင္နဲ႕ေ၀လငါးဟာ အသိဥာဏ္ရွိတဲ့ႏို႕တိုက္သတၱ၀ါျဖစ္လို႕ တခါတရံမွာ ...
Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C,T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the ...
Authors: Vázquez-Higuera, José Luis , Mateo, Ignacio , Sánchez-Juan, Pascual , Rodríguez-Rodríguez, Eloy , Pozueta, Ana , Calero, Miguel , Dobato, José Luis , Frank-García, Ana , Valdivieso, Fernando , Berciano, José , Bullido, Maria J. , Combarros, Onofre Article Type: Research Article Abstract: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimers disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was …an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) ...
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5-AMP-activated protein kinase catalytic subunit alpha-1 [ 3 ] [ 3D ]. 5-AMP-activated protein kinase catalytic subunit alpha ... 3-phosphoinositide-dependent protein kinase 1 (51-359) [ 964 ] [ 3D ]. 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) [ ... 3,5-cyclic phosphodiesterase [ 20 ] [ 3D ]. 3,5-cyclic phosphodiesterase (PDE2A) [ 560 ] [ 3D ]. 3-beta-hydroxysteroid ... 5-AMP-activated protein kinase subunit beta-1 [ 16 ] [ 3D ]. 5-AMP-activated protein kinase subunit gamma-1 [ 4 ] [ 3D ]. 5α- ...

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