Class II Phosphatidylinositol 3-Kinases: A subclass of phosphatidylinositol 3-kinases that have specificity for 1-phosphatidylinositol and 1-phosphatidylinositol 4-phosphate. Members of this subclass consist of a single subunit structure and are regulated by RECEPTOR TYROSINE KINASES; CYTOKINE RECEPTORS; and INTEGRINS.1-Phosphatidylinositol 4-Kinase: An enzyme that catalyzes the conversion of phosphatidylinositol (PHOSPHATIDYLINOSITOLS) to phosphatidylinositol 4-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.Phosphotransferases (Alcohol Group Acceptor): A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.Phosphatidylinositol 3-Kinases: 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.Phosphatidylinositol Phosphates: Phosphatidylinositols in which one or more alcohol group of the inositol has been substituted with a phosphate group.Phosphatidylinositol 4,5-Diphosphate: A phosphoinositide present in all eukaryotic cells, particularly in the plasma membrane. It is the major substrate for receptor-stimulated phosphoinositidase C, with the consequent formation of inositol 1,4,5-triphosphate and diacylglycerol, and probably also for receptor-stimulated inositol phospholipid 3-kinase. (Kendrew, The Encyclopedia of Molecular Biology, 1994)Histocompatibility Antigens Class II: Large, transmembrane, non-covalently linked glycoproteins (alpha and beta). Both chains can be polymorphic although there is more structural variation in the beta chains. The class II antigens in humans are called HLA-D ANTIGENS and are coded by a gene on chromosome 6. In mice, two genes named IA and IE on chromosome 17 code for the H-2 antigens. The antigens are found on B-lymphocytes, macrophages, epidermal cells, and sperm and are thought to mediate the competence of and cellular cooperation in the immune response. The term IA antigens used to refer only to the proteins encoded by the IA genes in the mouse, but is now used as a generic term for any class II histocompatibility antigen.Phosphatidylinositols: Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to the hexahydroxy alcohol, myo-inositol. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid, myo-inositol, and 2 moles of fatty acids.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.Genes, MHC Class II: Genetic loci in the vertebrate major histocompatibility complex that encode polymorphic products which control the immune response to specific antigens. The genes are found in the HLA-D region in humans and in the I region in mice.MAP Kinase Signaling System: 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.ChromonesAndrostadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.Phosphatidylinositol 3-Kinase: A phosphatidylinositol 3-kinase that catalyzes the conversion of 1-phosphatidylinositol into 1-phosphatidylinositol 3-phosphate.Signal Transduction: 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.MorpholinesProto-Oncogene Proteins c-akt: A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.Calcium-Calmodulin-Dependent Protein Kinases: 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)src-Family Kinases: A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes.Molecular Sequence Data: 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.Protein Kinase C: 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.Enzyme Activation: 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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Amino Acid Sequence: 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.Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.p38 Mitogen-Activated Protein Kinases: 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.Protein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.Mitogen-Activated Protein Kinase 1: 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.Protein Binding: 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.Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.DeoxycytidineMagnesium Sulfate: A small colorless crystal used as an anticonvulsant, a cathartic, and an electrolyte replenisher in the treatment of pre-eclampsia and eclampsia. It causes direct inhibition of action potentials in myometrial muscle cells. Excitation and contraction are uncoupled, which decreases the frequency and force of contractions. (From AMA Drug Evaluations Annual, 1992, p1083)Infusions, Intravenous: The long-term (minutes to hours) administration of a fluid into the vein through venipuncture, either by letting the fluid flow by gravity or by pumping it.Antineoplastic Combined Chemotherapy Protocols: The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.Drug Administration Schedule: Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience.Antimetabolites, Antineoplastic: Antimetabolites that are useful in cancer chemotherapy.Enzyme Precursors: Physiologically inactive substances that can be converted to active enzymes.HLA-B40 Antigen: A specific HLA-B surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-B*40 allele family.DNA-Activated Protein Kinase: A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.Lysosomes: A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured. Such rupture is supposed to be under metabolic (hormonal) control. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Endosomes: Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface.SulfonesNitriles: Organic compounds containing the -CN radical. The concept is distinguished from CYANIDES, which denotes inorganic salts of HYDROGEN CYANIDE.PyrazinesClass Ib Phosphatidylinositol 3-Kinase: A phosphatidylinositol 3-kinase subclass that includes enzymes formed through the association of a p110gamma catalytic subunit and one of the three regulatory subunits of 84, 87, and 101 kDa in size. This subclass of enzymes is a downstream target of G PROTEIN-COUPLED RECEPTORS.Patents as Topic: Exclusive legal rights or privileges applied to inventions, plants, etc.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Protein Isoforms: Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING.

Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. (1/22)

Activation of the phosphoinositide 3-kinases (PI 3-kinases) has been implicated in multiple cellular responses such as proliferation and survival, membrane and cytoskeletal reorganization, and intracellular vesicular trafficking. The activities and subcellular localization of PI 3-kinases were shown to be regulated by phosphorylation. Previously we demonstrated that class II HsPIK3-C2alpha becomes phosphorylated upon inhibition of RNA pol II-dependent transcription (Didichenko, S. A., and Thelen, M. (2001) J. Biol. Chem. 276, 48135-48142). In this study we investigated cell cycle-dependent and genotoxic stress-induced phosphorylation of HsPIK3-C2alpha. We find that the kinase becomes phosphorylated upon exposure of cells to UV irradiation and in proliferating cells at the G2/M transition of the cell cycle. Stress-dependent and mitotic phosphorylation of HsPIK3-C2alpha occurs on the same serine residue (Ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of HsPIK3-C2alpha can be attributed to Cdc2 activity, and stress-induced phosphorylation of HsPIK3-C2alpha is mediated by JNK/SAPK. The protein level of HsPIK3-C2alpha is regulated by proteolysis in a cell cycle-dependent manner and in response of cells to stress. Phosphorylation appears to be a prerequisite for proteasome-dependent degradation of HsPIK3-C2alpha and may therefore contribute indirectly to the regulation of the activity of the kinase.  (+info)

Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis. (2/22)

Neurotransmitter release and hormonal secretion are highly regulated processes culminating in the calcium-dependent fusion of secretory vesicles with the plasma membrane. Here, we have identified a role for phosphatidylinositol 3-kinase C2alpha (PI3K-C2alpha) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2alpha is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2alpha function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2alpha enhanced secretion, whereas transfection of PC12 cells with a catalytically inactive PI3K-C2alpha mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2alpha is required for acquisition of fusion competence in neurosecretion.  (+info)

Individual phosphoinositide 3-kinase C2alpha domain activities independently regulate clathrin function. (3/22)

Phosphoinositide 3-kinase C2alpha (PI3K-C2alpha) is a member of the class II PI-3 kinases, defined by the presence of a second C2 domain at their C termini. The cellular functions of the class II enzymes are incompletely understood, though they have been implicated in receptor activation pathways initiated by epidermal growth factor, insulin, and chemokines. PI3K-C2alpha was recently found to be localized to clathrin-coated membranes in the trans-Golgi network and at endocytic sites on the plasma membrane. Further, a specific binding site was identified for clathrin on the N terminus of PI3K-C2alpha, whose occupancy resulted in lipid kinase activation. Expression of PI3K-C2alpha in cells dramatically affected clathrin distribution and function in cells, leading to accumulation of intracellular clathrin-coated structures, which are visualized here at the ultrastructural level, and inhibition of clathrin-mediated transport from both the plasma membrane and the trans-Golgi network. In this study we have demonstrated that the isolated clathrin binding domain of PI3K-C2alpha can drive clathrin lattice assembly and that both it and the lipid kinase activity of the protein can independently modulate clathrin distribution and function when expressed in cells. Together, these results suggest that PI3K-C2alpha employs both protein-protein interaction and localized production of 3-phosphoinositides to affect clathrin dynamics at sites of membrane budding and targeting.  (+info)

The class II phosphoinositide 3-kinase C2beta is not essential for epidermal differentiation. (4/22)

Phosphoinositide 3-kinases (PI3Ks) regulate an array of cellular processes and are comprised of three classes. Class I PI3Ks include the well-studied agonist-sensitive p110 isoforms; however, the functions of class II and III PI3Ks are less well characterized. Of the three class II PI3Ks, C2alpha and C2beta are widely expressed in many tissues, including the epidermis, while C2gamma is confined to the liver. In contrast to the class I PI3K p110alpha, which is expressed throughout the epidermis, C2beta was found to be localized in suprabasal cells, suggesting a potential role for C2beta in epidermal differentiation. Overexpressing C2beta in epidermal cells in vitro induced differentiation markers. To study a role for C2beta in tissue, we generated transgenic mice overexpressing C2beta in both suprabasal and basal epidermal layers. These mice lacked epidermal abnormalities. Mice deficient in C2beta were then generated by targeted gene deletion. C2beta knockout mice were viable and fertile and displayed normal epidermal growth, differentiation, barrier function, and wound healing. To exclude compensation by C2alpha, RNA interference was then used to knock down both C2alpha and C2beta in epidermal cells simultaneously. Induction of differentiation markers was unaffected in the absence of C2alpha and C2beta. These findings indicate that class II PI3Ks are not essential for epidermal differentiation.  (+info)

Class II phosphoinositide 3-kinase alpha-isoform regulates Rho, myosin phosphatase and contraction in vascular smooth muscle. (5/22)

We demonstrated previously that membrane depolarization and excitatory receptor agonists such as noradrenaline induce Ca2+-dependent Rho activation in VSM (vascular smooth muscle), resulting in MP (myosin phosphatase) inhibition through the mechanisms involving Rho kinase-mediated phosphorylation of its regulatory subunit MYPT1. In the present study, we show in de-endothelialized VSM strips that the PI3K (phosphoinositide 3-kinase) inhibitors LY294002 and wortmannin inhibited KCl membrane depolarization- and noradrenaline-induced Rho activation and MYPT1 phosphorylation, with concomitant inhibition of MLC (20-kDa myosin light chain) phosphorylation and contraction. LY294002 also augmented de-phosphorylation of MLC and resultantly relaxation in KCl-contracted VSM, whereas LY294002 was much less effective or ineffective under the conditions in which MP was inhibited by either a phosphatase inhibitor or a phorbol ester in Rho-independent manners. VSM express at least four PI3K isoforms, including the class I enzymes p110alpha and p110beta and the class II enzymes PI3K-C2alpha and -C2beta. The dose-response relationships of PI3K-inhibitor-induced inhibition of Rho, MLC phosphorylation and contraction were similar to that of PI3K-C2alpha inhibition, but not to that of the class I PI3K inhibition. Moreover, KCl and noradrenaline induced stimulation of PI3K-C2alpha in a Ca2+-dependent manner, but not of p110alpha or p110beta. Down-regulation of PI3K-C2alpha expression by siRNA (small interfering RNA) inhibited contraction and phosphorylation of MYPT1 and MLC in VSM cells. Finally, intravenous wortmannin infusion induced sustained hypotension in rats, with inhibition of PI3K-C2alpha activity, GTP-loading of Rho and MYPT1 phosphorylation in the artery. These results indicate the novel role of PI3K-C2alpha in Ca2+-dependent Rho-mediated negative control of MP and thus VSM contraction.  (+info)

Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2alpha. (6/22)

Phox homology (PX) domains, which have been identified in a variety of proteins involved in cell signaling and membrane trafficking, have been shown to interact with phosphoinositides (PIs) with different affinities and specificities. To elucidate the structural origin of diverse PI specificities of PX domains, we determined the crystal structure of the PX domain from phosphoinositide 3-kinase C2alpha (PI3K-C2alpha), which binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). To delineate the mechanism by which this PX domain interacts with membranes, we measured the membrane binding of the wild type domain and mutants by surface plasmon resonance and monolayer techniques. This PX domain contains a signature PI-binding site that is optimized for PtdIns(4,5)P(2) binding. The membrane binding of the PX domain is initiated by nonspecific electrostatic interactions followed by the membrane penetration of hydrophobic residues. Membrane penetration is specifically enhanced by PtdIns(4,5)P(2). Furthermore, the PX domain displayed significantly higher PtdIns(4,5)P(2) membrane affinity and specificity when compared with the PI3K-C2alpha C2 domain, demonstrating that high affinity PtdIns(4,5)P(2) binding was facilitated by the PX domain in full-length PI3K-C2alpha. Together, these studies provide new structural insight into the diverse PI specificities of PX domains and elucidate the mechanism by which the PI3K-C2alpha PX domain interacts with PtdIns(4,5)P(2)-containing membranes and thereby mediates the membrane recruitment of PI3K-C2alpha.  (+info)

Phosphoinositide 3-kinase C2alpha links clathrin to microtubule-dependent movement. (7/22)

Phosphoinositide 3-kinase C2alpha (PI3K-C2alpha) is a type II PI-3-kinase that has been implicated in several important membrane transport and signaling processes. We previously found that overexpression of PI3K-C2alpha inhibits clathrin-mediated membrane trafficking and induces proliferation of novel clathrin-coated structures within the cytoplasm. Using fluorescently tagged fusions of PI3K-C2alpha and clathrin, we explored the behavior of these structures in intact cells. Both proteins are present in the structures, and using rapid image acquisition and fluorescence photoactivation probes, we find that they exhibit localized, rapid mobility (5-20 microm/s). The movement is micro-tubule-based as revealed by use of inhibitors, and PI3K-C2alpha accumulates on microtubules rapidly and reversibly following cytoplasmic acidification, which also blocks movement. Dynactin mediates the movement of these clathrin-PI3K-C2alpha structures, since disruption of dynactin function by overexpression of its p50 subunit also inhibits movement. Finally, immunoprecipitation experiments reveal an interaction between endogenous PI3K-C2alpha and dynactin subunits. Together, these results reveal a molecular linkage between PI3K-C2alpha and the microtubule motor machinery, with implications for membrane trafficking in intact cells.  (+info)

Ca2+-independent, inhibitory effects of cyclic adenosine 5'-monophosphate on Ca2+ regulation of phosphoinositide 3-kinase C2alpha, Rho, and myosin phosphatase in vascular smooth muscle. (8/22)

We have recently demonstrated in vascular smooth muscle (VSM) that membrane depolarization by high KCl induces Ca(2+)-dependent Rho activation and myosin phosphatase (MLCP) inhibition (Ca(2+)-induced Ca(2+)-sensitization) through the mechanisms involving phosphorylation of myosin-targeting protein 1 (MYPT1) and 17-kDa protein kinase C (PKC)-potentiated inhibitory protein of PP1 (CPI-17). In the present study, we investigated whether and how cAMP affected Ca(2+)-dependent MLCP inhibition by examining the effects of forskolin, cell-permeable dibutyryl cAMP (dbcAMP), and isoproterenol. Forskolin, but not its inactive analog 1,9-dideoxyforskolin, inhibited KCl-induced contraction and the 20-kDa myosin light chain (MLC) phosphorylation without inhibiting Ca(2+) mobilization in rabbit aortic VSM. dbcAMP mimicked these forskolin effects. We recently suggested that Ca(2+)-mediated Rho activation is dependent on class II alpha-isoform of phosphoinositide 3-kinase (PI3K-C2alpha). Forskolin inhibited KCl-induced stimulation of PI3K-C2alpha activity. KCl-induced membrane depolarization stimulated Rho in a manner dependent on a PI3K but not PKC and stimulated phosphorylation of MYPT1 at Thr(850) and CPI-17 at Thr(38) in manners dependent on both PI3K and Rho kinase, but not PKC. Forskolin, dbcAMP, and isoproterenol inhibited KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17. Consistent with these data, forskolin, isoproterenol, a PI3K inhibitor, or a Rho kinase inhibitor, but not a PKC inhibitor, abolished KCl-induced diphosphorylation of MLC. These observations indicate that cAMP inhibits Ca(2+)-mediated activation of the MLCP-regulating signaling pathway comprising PI3K-C2alpha, Rho, and Rho kinase in a manner independent of Ca(2+) and point to the novel mechanism of the cAMP actions in the regulation of vascular smooth muscle contraction.  (+info)

The family of PI3Ks (phosphatidylinositol 3-kinases) was discovered several decades ago, but until now most attention has been given to class I PI3Ks, mainly due to their previously established role in human disorders such as cancer and metabolic diseases. Class II PI3K has therefore been a bit in the shadow of the more intensively studied other families. Nevertheless, the number of reports about class II has started to increase over the past few years and we are now beginning to gain a clearer picture about the role of class II enzymes in different cellular functions and their involvement in human diseases. The fact that class II PI3K generates different second messengers (phosphoinositides) than the other PI3K family members, gives an indication that these enzymes might play a specific role in the regulation of distinct cellular functions. However, there is still a lot to be learned about the molecular mechanism of activation, the cellular function and the physiological and pathological role ...
Forschungsschwerpunkte:. - Signaltransduktion in soliden Tumoren. - Translationale Strategien im Bereich gastrointestinaler Tumoren, Biomarkerentwicklung und co-klinische 3D-Organoidkulturen. - Molekulare Regulation und Isoform-spezifische Funktion von Klasse I und II Phosphoinositid 3-Kinasen. - Onkogene Funktion von GTPasen der RAS und RHO Familien. Research interests:. - Signal transduction in solid tumours. - Translational research in GI malignancies, biomarker development, co-clinical 3D organoid cultures. - Molecular regulation and isoform-specific function of class I and II phosphoinositide 3-kinases (PI3Ks). - Oncogenic roles of small GTPases of the RAS and RHO families. ...
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Besenhard, J., Han, J-H., Wachtler, M., Möller, K-C., Wagner, M. R., Papst, I., Hofer, F., Park, H-Y., Park, S-Y., Lee, K-Y. & Winter, M., 23 Jun 2004.. Publikation: Konferenzbeitrag › (Altdaten) Vortrag oder Präsentation › Forschung ...
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Type II phosphatidylinositol (PtdIns) 4-kinases produce PtdIns 4-phosphate, an early key signaling molecule in phosphatidylinositol cycle, which is indispensable for T cell activation. Type II PtdIns 4-kinase alpha and beta have similar biochemical properties. To distinguish these isoforms Epigallocatechin gallate (EGCG) has been evaluated as a specific inhibitor. EGCG is the major active catechin in green tea having anti-inflammatory, antiatherogenic and cancer chemopreventive properties. The precise mechanism of actions and molecular targets of EGCG in early signaling cascades are not well understood. In the present study, we have shown that EGCG inhibits type II PtdIns 4-kinases (alpha and beta isoforms) and PtdIns 3-kinase activity in vitro. EGCG directly bind to both alpha and beta isoforms of type II PtdIns 4-kinases with a Kd of 2.62 mu M and 1.02 mu M, respectively. Type II PtdIns 4-kinase-EGCG complex have different binding pattern at its excited state. Both isoforms showed significant ...
Apoptotic cells generated by programmed cell death are engulfed by phagocytes and enclosed within membrane-bound phagosomes. Maturation of apoptotic cell-containing phagosomes leads to formation of phagolysosomes where cell corpses are degraded. The class III phosphatidylinositol 3-kinase (PI3-kinase) VPS-34 coordinates with PIKI-1, a class II PI3-kinase, to produce PtdIns3P on phagosomes, thus promoting phagosome closure and maturation. Here, we identified UBC-13, an E2 ubiquitin-conjugating enzyme that functions in the same pathway with VPS-34 but in parallel to PIKI-1 to regulate PtdIns3P generation on phagosomes. Loss of ubc-13 affects early steps of phagosome maturation, causing accumulation of cell corpses. We found that UBC-13 functions with UEV-1, a noncatalytic E2 variant, and CHN-1, a U-box-containing E3 ubiquitin ligase, to catalyze K63-linked poly-ubiquitination on VPS-34 both in vitro and in Caenorhabditis elegans. Loss of ubc-13, uev-1, or chn-1 disrupts ubiquitin modification of ...
K-C & More Powder supplement recommended to support a healthy circulatory system in horses. Vitamin K is known as a clotting factor. Veterinarian tested and recommended. Apple flavor.Each scoop contains 3,500 mg ascorbic acid (vitamin C) and 40 mg menadione (vitamin K).Directions: 1 scoop daily. 1 oz scoop enclosed. Safe use in pregnant animals o
Recent evidence suggests that concanavalin A modulates tyrosyl phosphorylation and activation of a type II PtdIns 4-kinase in rat splenic lymphocytes. However, the regulatory protein tyrosine kinase(s) remain to be elusive. The present manuscript provides evidence that a type II PtdIns 4-kinase associates with p56(lck) in Con A stimulated rat splenic lymphocytes. In vitro phosphorylation studies suggest that p561(lck) regulates phosphorylation and activation of type II PtdIns 4-kinase. Inhibition of p561(lck) activity in vivo has shown to reduce tyrosyl phosphorylation and activation of PtdIns 4-kinase by Con A. These results suggest that p56(lck) may be the physiological regulator of type II PtdIns 4-kinase ...
Expression of PIK3C2A (PI3K-C2alpha) in esophagus tissue. Antibody staining with HPA037641 and HPA037642 in immunohistochemistry.
The ARF proteins are categorized as class I (ARF1, ARF2,and ARF3), class II (ARF4 and ARF5) and class III (ARF6). The members ... 1999). "Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle ... Shin OH, Couvillon AD, Exton JH (2001). "Arfophilin is a common target of both class II and class III ADP-ribosylation factors ... Shin OH, Ross AH, Mihai I, Exton JH (2000). "Identification of arfophilin, a target protein for GTP-bound class II ADP- ...
This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3- ... Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing gamma polypeptide is an enzyme that in humans is encoded by the ... 1998). "A novel class II phosphoinositide 3-kinase predominantly expressed in the liver and its enhanced expression during ... 1998). "Cloning and characterization of a novel class II phosphoinositide 3-kinase containing C2 domain". Biochem. Biophys. Res ...
This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of Class II PI 3- ... Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the ... 2000). "The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin- ... 2000). "Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors". Mol. Cell ...
This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3- ... Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta polypeptide is an enzyme that in humans is encoded by the ... Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J (Jun 2000). "Class II phosphoinositide 3-kinases are ... Wheeler M, Domin J (Oct 2001). "Recruitment of the class II phosphoinositide 3-kinase C2beta to the epidermal growth factor ...
PIK3R2 and PIP5K1A are two Kinases that phosphorylate Phosphatidylinositol (PIP) providing PSD4 with substrates for its GTP ... Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α ... Histocompatibility Antigens Class II at the US National Library of Medicine Medical Subject Headings (MeSH) MHC Class II Genes ... The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to ...
Class II PI 3-kinases also appear to synthesise PtdIns3P, their activity however appears to be regulated by a range of stimuli ... P2 by the lipid kinase PIKfyve. Both FYVE domains and PX domains - found in proteins such as SNX1, Hrs, and EEA1 - bind to ... It is the product of both the class II and III phosphoinositide 3-kinases (PI 3-kinases) activity on phosphatidylinositol. ... Phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) is a phospholipid found in cell membranes that helps to recruit a range of ...
The age-1 gene encodes the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K). A decade after Johnson's ... one of the two genes that are essential for dauer larva formation, was shown by Cynthia Kenyon to double C. elegans lifespan. ... 22 (3-4): 279-286. doi:10.1016/0047-6374(83)90082-9. PMID 6632998. Friedman DB, Johnson TE (1988). "A mutation in the age-1 ... Kenyon showed that the daf-2 mutants, which would form dauers above 25 °C (298 K; 77 °F) would bypass the dauer state below 20 ...
... the two substrates of this enzyme are ATP and 1-phosphatidyl-1D-myo-inositol 4-phosphate, whereas its two products are ADP and ... The systematic name of this enzyme class is ATP:1-phosphatidyl-1D-myo-inositol-4-phosphate 3-phosphotransferase. Other names in ... In enzymology, a phosphatidylinositol-4-phosphate 3-kinase (EC 2.7.1.154) is an enzyme that catalyzes the chemical reaction ATP ... This enzyme participates in phosphatidylinositol signaling system. As of late 2007, 3 structures have been solved for this ...
"Findings of scientific misconduct". NIH Guide for Grants and Contracts / U.S. Department of Health, Education, and Welfare. 24 ... in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity". The Journal of Biological Chemistry ... It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor ... inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain". Genes to ...
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 1BO1 and 2GK9. Kai M, ... PIP kinase, phosphatidylinositol 4-phosphate kinase, phosphatidylinositol-4-phosphate 5-kinase, and type I PIP kinase. This ... In enzymology, 1-phosphatidylinositol-4-phosphate 5-kinase (EC 2.7.1.68) is an enzyme that catalyzes the chemical reaction ATP ... the two substrates of this enzyme are ATP and 1-phosphatidyl-1D-myo-inositol 4-phosphate, whereas its two products are ADP and ...
This enzyme is also called type II PIP kinase. This enzyme participates in 3 metabolic pathways: inositol phosphate metabolism ... The systematic name of this enzyme class is ATP:1-phosphatidyl-1D-myo-inositol-5-phosphate 4-phosphotransferase. ... In enzymology, a 1-phosphatidylinositol-5-phosphate 4-kinase (EC 2.7.1.149) is an enzyme that catalyzes the chemical reaction ... the two substrates of this enzyme are ATP and 1-phosphatidyl-1D-myo-inositol 5-phosphate, whereas its two products are ADP and ...
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 1INP and 1JP4. Berridge MJ ... This enzyme participates in inositol phosphate metabolism and phosphatidylinositol signaling system. ... the two substrates of this enzyme are 1D-myo-inositol 1,4-bisphosphate and H2O, whereas its two products are 1D-myo-inositol 4- ... The systematic name of this enzyme class is 1D-myo-inositol-1,4-bisphosphate 1-phosphohydrolase. This enzyme is also called ...
... some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase (MAPK) at high ... It displays a similar potency in vitro for the class I, II, and III PI3K members although it can also inhibit other PI3K- ... In 2010 PX-866 was starting 4 phase II trials for solid tumours. The company gave an update on its phase 2 trials in Jun 2012. ... "Phase II study of PX-866 in recurrent glioblastoma". Neuro Oncol. 17: 1270-4. doi:10.1093/neuonc/nou365. PMC 4588751 . PMID ...
All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP. Human MIC ... viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response ... "NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural ... In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D- ...
"Association of T cell antigen CD7 with type II phosphatidylinositol-4 kinase, a key component in pathways of inositol phosphate ... Bevec T, Stoka V, Pungercic G, Dolenc I, Turk V (April 1996). "Major histocompatibility complex class II-associated p41 ... Aruffo A, Seed B (November 1987). "Molecular cloning of two CD7 (T-cell leukemia antigen) cDNAs by a COS cell expression system ... Lee DM, Patel DD, Pendergast AM, Haynes BF (August 1996). "Functional association of CD7 with phosphatidylinositol 3-kinase: ...
It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also ... CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding". FASEB Journal ... IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, ... IL-10 is classified as a class-2 cytokine, a set of cytokines including IL-19, IL-20, IL-22, IL-24 (Mda-7), IL-26 and ...
... scavenger receptor class B type I (SR-BI) and lysosomal integral membrane protein II (LIMP-II). CD36 interacts with a number of ... Bull HA, Brickell PM, Dowd PM (August 1994). "Src-related protein tyrosine kinases are physically associated with the surface ... Unlike macropinocytosis this process is not affected by inhibitors of phosphatidylinositol 3-kinase or Na+/H+ exchange. CD36 ... In addition a role for CD36 has been found in the clearance of gametocytes (stages I and II). CD36 has been shown to have a ...
... and protein kinase C activity. Two enzymes, CDP-diacylglycerol synthase and phosphatidylinositol synthase, are involved in the ... Phosphatidylinositol synthase, a member of the CDP-alcohol phosphatidyl transferase class-I family, is an integral membrane ... Phosphatidylinositol breakdown products are ubiquitous second messengers that function downstream of many G protein-coupled ... Antonsson B (1997). "Phosphatidylinositol synthase from mammalian tissues". Biochim. Biophys. Acta. 1348 (1-2): 179-86. doi: ...
Class II and III PI3K are differentiated from the Class I by their structure and function. The distinct feature of Class II ... "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature. 332 (6165): ... Class I, Class II, Class III, and Class IV. The classifications are based on primary structure, regulation, and in vitro lipid ... Class II comprises three catalytic isoforms (C2α, C2β, and C2γ), but, unlike Classes I and III, no regulatory proteins. Class ...
... phosphatidylinositol 4-kinase, phosphatidylinositol kinase, type II phosphatidylinositol kinase, PI kinase, and PI 4-kinase. ... The systematic name of this enzyme class is ATP:1-phosphatidyl-1D-myo-inositol 4-phosphotransferase. Other names in common use ... "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature. 332 (6165): ... In enzymology, a 1-phosphatidylinositol 4-kinase (EC 2.7.1.67) is an enzyme that catalyzes the chemical reaction ATP + 1- ...
... like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors ... A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be ... Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)- ... First, two kinases, ATM and ATR are activated within 5 or 6 minutes after DNA is damaged. This is followed by phosphorylation ...
NGF binds with at least two classes of receptors: the tropomyosine receptor kinase A (TrkA) and low-affinity NGF receptor ( ... Crowder RJ, Freeman RS (Apr 1998). "Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the ... A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase (MAPK) kinase ... Two other patients received direct injections of modified viruses containing the NGF gene directly to their basal forebrains. ...
This similarity increases to ~ 70% across PKCs and even higher when comparing within classes. For example, the two atypical PKC ... It is presumed that this is achieved by the production of diacylglycerol from phosphatidylinositol by a phospholipase; fatty ... Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in ... The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it contains basic amino acids ...
Akt also phosphorylates MAP kinase kinase kinases (MAPKKK) upstream of the stress-activated protein kinase (SAPK) pathway. ... Class 1 PI3Ks are heterodimers composed of a regulatory subunit p85 and a catalytic subunit p110, named by their molecular ... This has been linked to a range of diseases such as cancer and type II diabetes. A major antagonist of PI3K activity is PTEN ( ... Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt (Protein Kinase B). Initial stimulation by one of the ...
Dual-specificity kinases are subclass of the tyrosine kinases. mTOR is a kinase within the family of phosphatidylinositol-3 ... protein kinases are classified in two major categories based on their substrate specificity, protein tyrosine kinases and ... and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC- ... The serine/threonine kinase mTOR is a downstream effector of the PI3K/AKT pathway, and forms two distinct multiprotein ...
These two kinases regulate autophagy through inhibitory phosphorylation of the Unc-51-like kinases ULK1 and ULK2 (mammalian ... The autophagy-inducible Beclin-1 complex[40] contains the proteins p150, Atg14L and the class III phosphatidylinositol 3- ... E. Itakura, C. Kishi, K. Inoue, and N. Mizushima, 'Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with ... Once active, VPS34 phosphorylates the lipid phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns(3)P) on ...
We now show that the class II phosphatidylinositol 3 kinase C2beta (PI3K-C2beta) is activated by the T-cell receptor (TCR) and ... This is the first demonstration that a class II PI3K plays a critical role in T-cell activation. ... We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates ... The inhibition was due to decreased phosphatidylinositol 3-phosphate [PI(3)P] because dialyzing PI3K-C2beta siRNA-treated T- ...
Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 ... Phase 1 Study of PI3 (Phosphatidylinositol-3)-Kinase Inhibitor Copanlisib With Gemcitabine or Cisplatin Plus Gemcitabine in ... Phase 1 Study of PI3 (Phosphatidylinositol-3)-Kinase Inhibitor Copanlisib With Gemcitabine or Cisplatin Plus Gemcitabine in ... A Phase 1 Study of Copanlisib(Phosphatidylinositol-3 Kinase Inhibitor) in Combination With Gemcitabine (Treatment A) or ...
Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are ... class III, type II Source: GO_Central. *pre-autophagosomal structure Source: GO_Central ... IPR011009. Kinase-like_dom_sf. IPR000403. PI3/4_kinase_cat_dom. IPR036940. PI3/4_kinase_cat_sf. IPR018936. PI3/4_kinase_CS. ... IPR011009. Kinase-like_dom_sf. IPR000403. PI3/4_kinase_cat_dom. IPR036940. PI3/4_kinase_cat_sf. IPR018936. PI3/4_kinase_CS. ...
... class III, type II, 1-phosphatidylinositol-3-kinase activity, autophagosome assembly, autophagy of peroxisome ... phosphatidylinositol 3-kinase complex, class III, type I, phosphatidylinositol 3-kinase complex, ... IPR011009 Kinase-like_dom_sf. IPR000403 PI3/4_kinase_cat_dom. IPR036940 PI3/4_kinase_cat_sf. IPR018936 PI3/4_kinase_CS. ... IPR011009 Kinase-like_dom_sf. IPR000403 PI3/4_kinase_cat_dom. IPR036940 PI3/4_kinase_cat_sf. IPR018936 PI3/4_kinase_CS. ...
Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are ... class III, type II Source: GO_CentralInferred from biological aspect of ancestori*21873635 ... IPR011009 Kinase-like_dom_sf. IPR000403 PI3/4_kinase_cat_dom. IPR036940 PI3/4_kinase_cat_sf. IPR018936 PI3/4_kinase_CS. ... IPR011009 Kinase-like_dom_sf. IPR000403 PI3/4_kinase_cat_dom. IPR036940 PI3/4_kinase_cat_sf. IPR018936 PI3/4_kinase_CS. ...
... class I or II); PIP5K, 1-phosphatydylinositol-4-phosphate 5-kinase; PIG-P, phosphatidyl-inositolglycan-peptide; PDK1, 3- ... phosphoinositide-dependent kinase 1; PKB, protein kinase B; HR46, honeybee ortholog of Dmel/HR46; PTEN, phosphatidylinositol-3, ... Two-way selection for pollen hoarding revealed a complex phenotypic, hormonal and genetic architecture affecting division of ... Figure 2. The top panel demonstrates the proboscis extension reflex of a restrained worker honey bee. A droplet of sucrose is ...
Association functional classification system (NYHA) Class II; active coronary artery. disease, myocardial infarction within 6 ... We are a Cancer Social Network, Resource Directory & Education Hub supporting all those affected by cancer. knowcancer.com is ... A Phase 1 Study of BAY80-6946 (Phosphatidylinositol-3 Kinase Inhibitor) in Combination With Gemcitabine (Treatment A) or ... A Phase 1 Study of BAY80-6946 (Phosphatidylinositol-3 Kinase Inhibitor) in Combination With Gemcitabine (Treatment A) or ...
... lipid kinase activity (inferred); phosphatidylinositol binding (inferred); INVOLVED IN macroautophagy (ortholog); ASSOCIATED ... ENCODES a protein that exhibits kinase activity (inferred); ... class 2, beta polypeptide. Orthologs:. Homo sapiens (human) : ... ENCODES a protein that exhibits kinase activity (inferred); lipid kinase activity (inferred); phosphatidylinositol binding ( ... phosphatidylinositol kinase activity IBA. FB:FBgn0015277 more .... 13508589. (PMID:21873635). GO_Central. PMID:21873635. ...
J:46628 Misawa H, et al., Cloning and characterization of a novel class II phosphoinositide 3-kinase containing C2 domain. ... Vertebrate Homology Class 3362. 1 human;1 mouse;1 rat;1 chimpanzee;1 cattle;1 dog;1 chicken;1 zebrafish;1 macaque, rhesus. ... IPR000403 Phosphatidylinositol 3-/4-kinase, catalytic domain. IPR036940 Phosphatidylinositol 3-/4-kinase, catalytic domain ... PIK3C2G, phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma. Orthology source: HomoloGene, HGNC ...
... phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha), Authors: Dessen P. Published in: Atlas Genet ... class 2, alpha polypeptide. phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 alpha. ... ARM-type_fold C2_dom C2_domain_sf Kinase-like_dom_sf Phox PI3/4_kinase_cat_dom PI3/4_kinase_cat_sf PI3/4_kinase_CS PI3K-C2- ... C2 (PS50004) PI3_4_KINASE_1 (PS00915) PI3_4_KINASE_2 (PS00916) PI3_4_KINASE_3 (PS50290) PI3K_C2 (PS51547) PI3K_RBD (PS51546) ...
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 1BO1 and 2GK9. Kai M, ... PIP kinase, phosphatidylinositol 4-phosphate kinase, phosphatidylinositol-4-phosphate 5-kinase, and type I PIP kinase. This ... In enzymology, 1-phosphatidylinositol-4-phosphate 5-kinase (EC 2.7.1.68) is an enzyme that catalyzes the chemical reaction ATP ... the two substrates of this enzyme are ATP and 1-phosphatidyl-1D-myo-inositol 4-phosphate, whereas its two products are ADP and ...
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including ... Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including ... The differential regulation of class I PI3K genes further divides this class into two subclasses: IA and IB. The class IA PI3K ... Class I PI3K genes control the activity of PI3K/AKT signaling and are often genetically altered in glioblastoma (29). Class II ...
26 ), phosphatidylinositol 3′-kinase (e.g., LY294002; Ref. 27 ), protein kinase C (staurosporine; Ref. 28 ), cyclin-dependent ... This in vitro assay was performed using a PDK-1 kinase assay kit (Upstate) according to the vendors instructions. This cell- ... This mode of inhibition (i.e., ATP competition) is common among numerous classes of protein or lipid kinase inhibitors that ... Values represent the means of two independent determinations.. Immunoprecipitated p70 S6 kinase (p70S6K) Assay.. ...
Class II Phosphatidylinositol 3-Kinases). ... protein kinase B (Akt) signaling pathway, of which the PI3K-γ ... MATERIALS AND METHODS: Cytotoxicity against two human oral squamous cell carcinoma cell lines and two human normal oral ... Classe II de Fosfatidilinositol 3-Quinases/metabolismo. Sepse/complica es. [Mh] Termos MeSH secund rio:. Animais. ... Classe II de Fosfatidilinositol 3-Quinases/gen tica. Citocinas/sangue. Modelos Animais de Doen as. Regula o para Baixo. ...
Acts as core subunit of different PI3K complex forms that mediate formation of phosphatidylinositol 3-phosphate and are ... "The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy.". Dou Z., Chattopadhyay M., ... class III, type II Source: GO_CentralInferred from biological aspect of ancestori*. "Phylogenetic-based propagation of ... "Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic ...
Phosphatidylinositol kinases. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance ... class 2, alpha polypeptide , PI3KC2 , PI3K-C2alpha , phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 alpha ... Phosphatidylinositol kinases: phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha. Last modified on 29/01/ ... phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha Rat. -. 1687. 1 q34-q35. Pik3c2a phosphatidylinositol- ...
The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are ... useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform. ... 150000001875 compounds Chemical class 0 abstract claims description 278 * 102000003993 Phosphatidylinositol 3-kinases Human ... 108090000430 Phosphatidylinositol 3-kinases Proteins 0 abstract claims description 50 * 201000010099 diseases Diseases 0 ...
P13K class 2 signaling. Protein. PIP3. FGFR1. TSC1. P16. ERRFI1. PTEN. RB1. PIK3C2B. MAP2K1. PDPK1. SPRY2. GRB2. PI(3)P. AKT1. ... two-thirds there. 50105. view. 20:46, 7 August 2012. AlexanderPico. Periodical save, work in progress. 50104. view. 20:35, 7 ... Ontology Term : protein kinase C (PKC) signaling pathway added !. 50167. view. 21:16, 8 August 2012. AlexanderPico. Ontology ... Ontology Term : phosphatidylinositol 3-kinase class II signaling pathway added !. 50165. view. 21:16, 8 August 2012. ...
P13K class 1 / AKT signaling. PDGFRA. PDGFRB. ERBB2. EGFR. FGFR2. MET. FOXO. ATK. CBL. NF1. NRAS. KRAS. HRAS. RAS. ARAF. BRAF. ... two-thirds there. 50105. view. 20:46, 7 August 2012. AlexanderPico. Periodical save, work in progress. 50104. view. 20:35, 7 ... Ontology Term : protein kinase C (PKC) signaling pathway added !. 50167. view. 21:16, 8 August 2012. AlexanderPico. Ontology ... Ontology Term : phosphatidylinositol 3-kinase class II signaling pathway added !. 50165. view. 21:16, 8 August 2012. ...
Reduced IL-4-, lipopolysaccharide-, and IFN-gamma-induced MHC class II expression in mice lacking class II transactivator due ... Downregulation of CIITA function by protein kinase a (PKA)-mediated phosphorylation: mechanism of prostaglandin E, cyclic AMP, ... Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen- ... Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator ...
Involvement of class II phosphoinositide 3-kinase α-isoform in antigen-induced degranulation in RBL-2H3 cells. ... Phosphatidylinositol Phosphates/metabolism. *RAW 264.7 Cells. *RNA, Messenger/genetics/metabolism. *RNA, Small Interfering/ ... Involvement of class II phosphoinositide 3-kinase α-isoform in antigen-induced degranulation in RBL-2H3 cells. ... In this study, we present findings that suggest that PI3K-C2α, a member of the class II phosphoinositide 3-kinase (PI3K) ...
Two predominant receptor classes are the G-protein-coupled receptor class and the receptor tyrosine kinase class. Extracellular ... Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature. 390, 1997a 410- ... Ca2+/calmodulin-dependent protein kinase II is stimulated by Wnt and frizzled homologs and promotes ventral cell fates in ... including PKC and Ca2+/calmodulin-dependent protein kinase II (CaMKII; Nadif Kasri et al. 2002; Assefa et al. 2004; Patterson ...
Functional Class Functional class of the sequence domain architecture. * Gene neighbors Overlapping genes and two nearest non- ... PI3-kinase regulatory subunit gamma. PI3-kinase subunit p55-gamma. PI3K regulatory subunit gamma. phosphatidylinositol 3-kinase ... The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their ... Type II diabetes mellitus, conserved biosystem (from KEGG) Type II diabetes mellitus, conserved biosystemInsulin resistance is ...
Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell. 19:5360- ... and should not be confused with the mammalian class I and class II PI3Ks. Most recently there has been an explosion of new ... Molecules involved in the induction of autophagy: Atg proteins, Rab proteins, and the class III PI3 kinase. The source of the ... Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. Anne Simonsen, Sharon A. Tooze ...
"Findings of scientific misconduct". NIH Guide for Grants and Contracts / U.S. Department of Health, Education, and Welfare. 24 ... in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity". The Journal of Biological Chemistry ... It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor ... inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain". Genes to ...
  • We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. (ox.ac.uk)
  • This lipid is present in low amounts in mammalian cells and remains difficult to quantify either by traditional techniques based on radiolabelling followed by HPLC to separate the different phosphatidylinositol monophosphates, or by high-sensitive liquid chromatography coupled to MS, which is still under development. (pubmedcentralcanada.ca)
  • Five functional modules have been defined: The first module is the ULK1 complex (ULK1 is the mammalian homolog of yeast Atg1), the second module is the phosphatidylinositol 3-kinase (PIK3) complex I (which contains PIK3C3/Vps34), and Beclin 1 (Beclin 1 or BECN1 being the mammalian homolog of the yeast Atg6). (springer.com)
  • The last functional module consists of the two ubiquitin-like conjugation systems: ATG12-ATG5 and the LC3-phosphatidylethanolamine (PE) (LC3 being the mammalian homolog of yeast Atg8), which are involved in the elongation and closure of the autophagosomal membrane [ 15 , 16 ]. (springer.com)
  • In mammalian cells three classes of PI 3-kinases have been identified in addition to a Vps34 homolog ( 2 ). (sciencemag.org)
  • The mammalian target of rapamycin (mTOR) kinase is implicated in the regulation of initiation of mRNA translation, cell cycle progression, and cellular proliferation. (aacrjournals.org)
  • It is composed of ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR). (wikipedia.org)
  • mTORC1 consists of mTOR and two positive regulatory subunits, raptor and mammalian LST8 (mLST8), and two negative regulators, proline-rich AKT substrate 40 (PRAS40) and DEPTOR. (wikipedia.org)
  • In mammalian Inositol-trisphosphate 3-kinases, there are two major functional domains. (wikipedia.org)
  • The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. (wikipedia.org)
  • That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. (wikipedia.org)
  • Oxidative stress increases the formation of the complex formed with RPTOR, G3BP1, and SPAG5 RPTOR has also been shown to interact with: FKBP1A, P70-S6 Kinase 1 RHEB, RICTOR, and mammalian target of rapamycin (mTOR), The clinical significance of RPTOR is primarily due to its involvement in the mTOR pathway, which plays roles in mRNA translation, autophagy, and cell growth. (wikipedia.org)
  • Crystal structures of C2ALPHA-PI3 kinase PX-domain domain indicate conformational change associated with ligand binding. (guidetopharmacology.org)
  • Direct activation of human dendritic cells by particle-bound but not soluble MHC class II ligand. (invivogen.com)
  • These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. (wikipedia.org)
  • A binding site in the extracellular N-terminal ligand-binding domain gives them receptor specificity for (1) acetylcholine (AcCh), (2) serotonin, (3) glycine, (4) glutamate and (5) γ-aminobutyric acid (GABA) in vertebrates. (wikipedia.org)
  • The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand. (wikipedia.org)
  • The overall 3D ectodomain structure, possessing four ligand binding sites, resembles an inverted 'V', with the each monomer rotated approximately 2-fold about an axis running parallel to the inverted 'V' and L2 and FnIII-1 domains from each monomer forming the inverted 'V's apex. (wikipedia.org)
  • A receptor tyrosine kinase is a "tyrosine kinase" which is located at the cellular membrane, and is activated by binding of a ligand to the receptor's extracellular domain. (wikipedia.org)
  • nearly 100% of glioblastoma patients will succumb to tumor recurrence if they live more than 2 years. (frontiersin.org)
  • Tumor assessments will be done at Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months during Year 3. (clinicaltrials.gov)
  • Autophagy is involved in the adaptation to starvation, in cell differentiation and development, as well as in the degradation of aberrant structures, the turnover of organelles, tumor suppression, innate and adaptive immunity, life span extension, and cell death [ 2 , 3 ]. (springer.com)
  • Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. (medscape.com)
  • PI-3-K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. (wikipedia.org)
  • Inhibiting PI-3-K presents the opportunity to inhibit a major cancer cell survival signaling pathway and to overcome the action of an important deleted tumor suppressor, providing antitumor activity and increased tumor sensitivity to a wide variety of drugs. (wikipedia.org)
  • Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. (aacrjournals.org)
  • Selective elimination of tumor-associated endothelial cells is the goal of antiangiogenic therapeutic strategies that are being used today for the treatment of cancer ( 2 , 3 ). (aacrjournals.org)
  • While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumour heterogeneity. (wikipedia.org)
  • Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. (wikipedia.org)
  • Deffrennes V, Vedrenne J, Stolzenberg MC, Piskurich J, Barbieri G, Ting JP, Charron D, Alcaide-Loridan C. Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter . (unc.edu)
  • A decade after Johnson's discovery daf-2, one of the two genes that are essential for dauer larva formation, was shown by Cynthia Kenyon to double C. elegans lifespan. (wikipedia.org)
  • NGF can drive the expression of genes such as bcl-2 by binding to the TrkA receptor, which stimulates the proliferation and survival of the target neuron. (wikipedia.org)
  • The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. (wikipedia.org)
  • Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1993. (wikipedia.org)
  • Other names in common use include diphosphoinositide kinase, PIP kinase, phosphatidylinositol 4-phosphate kinase, phosphatidylinositol-4-phosphate 5-kinase, and type I PIP kinase. (wikipedia.org)
  • Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. (jci.org)
  • 1998). "A type II phosphoinositide 3-kinase is stimulated via activated integrin in platelets. (wikipedia.org)
  • This modification is catalyzed by type I and II protein-arginine methyltransferases (PRMT), respectively. (mcponline.org)
  • and one type II, PRMT5 ( 8 ). (mcponline.org)
  • Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. (springer.com)
  • No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. (springer.com)
  • Obesity and type 2 diabetes are serious threats to public health that are reaching epidemic proportions worldwide. (springer.com)
  • Knockdown of Bcl-2 in HeLa cells with siRNA resulted in an increase in the number of autophagic structures under starvation conditions compared with those observed in starved cells with wild-type levels of Bcl-2. (sciencemag.org)
  • In MCF7 cells (which do not have wild-type beclin 1), expression of mutant forms of beclin 1 that could not bind Bcl-2 caused an increase in basal, as well as starvation-induced, autophagic structures. (sciencemag.org)
  • Other names in common use include type II phosphoinositide 3-kinase, C2-domain-containing phosphoinositide 3-kinase, and phosphoinositide 3-kinase. (wikipedia.org)
  • OBJECTIVE It remains unclear how many hours of sleep are associated with the lowest risk of type 2 diabetes. (diabetesjournals.org)
  • This meta-analysis was performed to assess the dose-response relationship between sleep duration and risk of type 2 diabetes. (diabetesjournals.org)
  • RESEARCH DESIGN AND METHODS PubMed and Embase were searched up to 20 March 2014 for prospective observational studies that assessed the relationship of sleep duration and risk of type 2 diabetes. (diabetesjournals.org)
  • A total of 18,443 incident cases of type 2 diabetes were ascertained among 482,502 participants with follow-up periods ranging from 2.5 to 16 years. (diabetesjournals.org)
  • A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7-8 h per day. (diabetesjournals.org)
  • Both short and long sleep duration are associated with a significantly increased risk of type 2 diabetes, underscoring the importance of appropriate sleep duration in the delay or prevention of type 2 diabetes. (diabetesjournals.org)
  • Several studies have reported a U-shaped association between sleep duration and type 2 diabetes ( 8 , 9 ), but other studies have not found a uniform relationship ( 10 , 11 ). (diabetesjournals.org)
  • One previous meta-analysis suggested that both short and long sleep duration were associated with risk of type 2 diabetes ( 12 ). (diabetesjournals.org)
  • In addition, without a dose-response analysis, it remains unknown how many hours of habitual sleep are associated with the lowest risk of type 2 diabetes. (diabetesjournals.org)
  • Therefore, we conducted a meta-analysis of prospective studies to determine the overall shape of the relationship between sleep duration and risk of type 2 diabetes. (diabetesjournals.org)
  • We conducted a literature search (up to 20 March 2014) of PubMed (Medline) and Embase for prospective studies examining the association between sleep duration and risk of type 2 diabetes. (diabetesjournals.org)
  • may be involved in type II PCD in cancer cells, could limit cell size or may remove damaged organelles that could generate free radicals and increase mutations. (sciencemag.org)
  • However this does not mean that these processes are any less important than MaA, as numerous studies have identified an association between various diseases (Parkinson's disease, Alzheimer's disease, type-II diabetes, obesity, cardiovascular disease, and cancer) and generally unregulated or defective autophagy processes [ 5 - 12 ]. (hindawi.com)
  • OBJECTIVE- We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI. (diabetesjournals.org)
  • Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis, and BMI and nonparametric linkage analyses. (diabetesjournals.org)
  • Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis, BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. (diabetesjournals.org)
  • RESULTS- The strongest signal for type 2 diabetes (logarithm of odds [LOD] 4.53) was a broad peak on chromosome 2, with weaker linkage to age of type 2 diabetes diagnosis (LOD 1.82). (diabetesjournals.org)
  • Type 2 diabetes is marked by a clear genetic propensity, a high concordance in identical twins, tendencies for both diabetes and age of onset to be familial ( 1 ), and marked differences in prevalence among ethnic groups ( 2 ). (diabetesjournals.org)
  • Thus, the genetic predisposition for type 2 diabetes in minority populations remains largely unknown. (diabetesjournals.org)
  • Previous genome-wide linkage scans for type 2 diabetes in African American or African families have been limited. (diabetesjournals.org)
  • Other names in common use include phosphatidylinositol kinase (phosphorylating), phosphatidylinositol 4-kinase, phosphatidylinositol kinase, type II phosphatidylinositol kinase, PI kinase, and PI 4-kinase. (wikipedia.org)
  • This has been linked to a range of diseases such as cancer and type II diabetes. (wikipedia.org)
  • Mast cells in rodents are classically divided into two subtypes: connective tissue-type mast cells and mucosal mast cells. (wikipedia.org)
  • DP2 was found to stimulate the directed movement or chemotaxis of human T-helper type 2 cells (see T helper cell#Th1/Th2 Model for helper T cells) by binding to a receptor initially termed GPR44 and thereafter CRTH2 (for Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells). (wikipedia.org)
  • They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. (wikipedia.org)
  • Interferon type II (IFN-γ in humans): This is also known as immune interferon and is activated by Interleukin-12. (wikipedia.org)
  • Furthermore, type II interferons are released by T helper cells, type 1 specifically. (wikipedia.org)
  • However, they block the proliferation of T helper cells type two. (wikipedia.org)
  • Although discovered more recently than type I and type II IFNs, recent information demonstrates the importance of Type III IFNs in some types of virus infections. (wikipedia.org)
  • In general, type I and II interferons are responsible for regulating and activating the immune response. (wikipedia.org)
  • JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. (wikipedia.org)
  • In type 2 diabetes mellitus the destruction of beta cells is less pronounced than in type 1 diabetes, and is not due to an autoimmune process. (wikipedia.org)
  • The pathogenesis of type 2 diabetes is not well understood but patients exhibit a reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive and peripheral tissue insulin resistance. (wikipedia.org)
  • Type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, and unresponsive to the concentration of glucose in the blood glucose. (wikipedia.org)
  • These two complexes (modules) are involved in the initiation of autophagy. (springer.com)
  • 73 Myopathy, X-linked, with excessive autophagy: A muscle disorder characterized by childhood early onset of a slowly progressive proximal limb muscle weakness (especially in legs) and elevation of serum creatine kinase, without evidence of cardiac, respiratory or central nervous system involvement. (malacards.org)
  • Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. (nih.gov)
  • In addition to turnover of cellular components, autophagy is involved in development, differentiation, and tissue remodeling in various organisms ( 2 ). (sciencemag.org)
  • BECN1 has been shown to interact with: Bcl-2 BCL2L2 GOPC MAP1LC3A Trehalose Trehalose reduces p62/Beclin-1 ratio and increases autophagy in the frontal cortex of ICR mice, possibly by increasing Beclin-1. (wikipedia.org)
  • It was first shown by Shen and co-workers ( 23 ) that the removal of the yeast methyltransferase Hmt1p causes the nuclear retention of two hnRNPs, Npl3p and Hrp1p. (mcponline.org)
  • In yeast, the forward direction is Mg 2 + {\displaystyle {\ce {Mg^{2+}}}} -dependent, while the reverse direction is Ca 2 + {\displaystyle {\ce {Ca^{2+}}}} -dependent. (wikipedia.org)
  • It was also independently discovered in Sandra Citi's group as a protein interacting with globular head domain of the Paracingulin in a yeast two-hybrid screen. (wikipedia.org)
  • a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway (such as those that would be loaded onto class I MHC). (wikipedia.org)
  • Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL-2 and Beclin1. (nih.gov)
  • Tubulin can also be phosphorylated by several kinases ( 11 ), and such changes affect the overall dynamic properties of cellular microtubules during interphase as well as mitosis ( 11 - 14 ). (aacrjournals.org)
  • Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients. (wikipedia.org)
  • This kinase has been shown to be involved in many different cellular functions, such as apoptosis, cardioprotection from ischemia, heat shock response, as well as insulin exocytosis. (wikipedia.org)