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evolution
three enzymes belong to the class II subfamily, PI3K-C2alpha, beta, and gamma
evolution
PI3K enzyme sequence comparisons
malfunction
agonist-induced 3-phosphorylated phosphoinositide production and cellular activation are normal in PI3KC2alpha-deficient platelets. PI3KC2alpha deficiency exacerbates bleeding and impairs thrombosis. Phenotype of Pik3c2alpha-/- mice. PI3KC2alpha deficiency alters platelet and megakaryocyte internal membrane structures, overview. PI3KC2alpha deficiency causes unstable platelet thrombi and enhances shear-dependent platelet adhesion
malfunction
downregulation of PI3K-C2beta in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. PI3K-C2beta inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo
malfunction
inhibition of MEK/ERK activation as well as downregulation of PI3K-C2beta does not affect cell proliferation while specifically inhibiting cell invasion
malfunction
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PI3K-C2alpha knockdown decreases the FceRI-triggered release of a lysosomal enzyme, namely beta-hexosaminidase, protein levels of PI3K-C2beta are not significantly affected by the shRNAs. siRNA against PI3K-C2beta impairs the FceRI-induced increase in intracellular Ca2+ and degranulation. Release of NPY-mRFP, a reporter of the regulated exocytosis of mast cells is increased by PI3K-C2alpha overexpression and is impaired in the PI3K-C2alpha-deficient cells
malfunction
PI3KC2beta-silencing inhibits early stages of neuroblastoma tumorigenic growth, but does not alter apoptotic or endocytic pathways, and silencing of the enzyme's regulator intersectin 1, ITSN1, also dramatically reduces the tumorigenic potential of neuroblastoma cells. Overexpression of PI3KC2beta rescues the anchorage-independent growth of ITSN1-silenced cells suggesting that PI3KC2beta mediates ITSN1's function in neuroblastoma cells. Silencing ITSN1 or PI3KC2beta decreases AKT activation in neuroblastoma cells
malfunction
TGFbeta1 stimulated nuclear accumulation of p-Smad2 is markedly suppressed by PI3K-C2alpha knockdown. Effect of PI3K-C2alpha knockdown on the co-localization of TGFbeta1 receptors and SARA. PI3K-C2alpha knockdown does not affect the numbers of either SARA-positive or EEA1-positive vesicles in nonstimulated cells but abolished TGFbeta1-induced increase in SARA- and EEA1-double positive early endosomes
malfunction
different deficiency types of PI3KC2alpha can cause different phenotypes, including stunted growth, decreased survival, renal abnormalities, embryonic lethality, decreased retinal angiogenesis, impaired revascularization following ischemic injury, and impaired platelet function during thrombosis. Mouse models of PI3KC2alpha deficiency. While homozygosity for kinase-dead PI3KC2alpha is embryonic lethal, heterozygous PI3KC2alpha KI mice are viable and fertile, with no significant histopathological findings. Male heterozygous mice show early onset leptin resistance, with a defect in leptin signaling in the hypothalamus, correlating with a mild, age-dependent obesity, insulin resistance, and glucose intolerance
malfunction
downregulation of PI3KC2beta results the inhibition of early stage neuroblastoma formation. Serum-dependent lamellipodia formation has been significantly reduced in cells lacking PI3KC2beta. Selective inhibition of PI3KC2beta with ceramide has been shown to diminish PI3KC2beta-dependent lamellipodia formation, reducing ovarian cancer cell mobility. Blocking of PI3KC2? pathway results in the impairment of SKOV3 cell migration. Depletion of PI3KC2beta can increase resistance of cells to chemotherapeutics
malfunction
effects of LY294002, sevoflurane (SEVO) and isoflurane (ISO) on KCl-elicited PI3KC2alpha mediated vasoconstriction in rat aortic smooth muscle, overview. PI3K inhibitor LY294002 inhibits PI3K-C2alpha membrane translocation in response to KCl. SEVO and ISO inhibit KCl-stimulated MLC phosphorylation, PI3K-C2alpha and Rock-II, but not PI3K p85, membrane translocation in a concentration-dependent manner in rat aorta
malfunction
global deficiency of PI3KC2gamma causes a phenotype of hyperlipidemia, adiposity, and insulin resistance
malfunction
heterozygous kinase-dead inactivating mutation of PI3KC2gamma causes a phenotype of decreased circulating insulin levels, increased glucose tolerance, and protection against steatosis. Inhibition of PI3KC2beta significantly reduced ovarian cancer metastasis in mice
malfunction
ITSN1 knockdown dramatically reduces the localization of PI3K-C2beta at actin patches and at clathrin-coated structures
malfunction
knockdown of PI3K-C2alpha inhibits internalization of cell surface molecules
malfunction
PI3KC2alpha mRNA is downregulated in islets from type 2 diabetic patients compared to nondiabetic individuals. PI3KC2alpha plays a sex-dependent role in the modulation of hypothalamic leptin action and systemic glucose homeostasis
malfunction
PI3KCb and PI3KC2a mRNA levels re significantly lower in insulin + wortmannin group than those in single insulin group
metabolism
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involvement of PI3K-C2alpha in the antigen-induced degranulation pathway
metabolism
insulin treatment shows no significant effect on GDH activity and mRNA expression of PI3KCa, PI3KCd, PI3KCg, PI3KC2b, PI3KC3 and eEF2 both in the in vivo and in vitro studies. Among seven PI3K members, PI3KCb and PI3KC2a are more sensitive to the insulin signaling pathway, and insulin stimulates hepatic protein synthesis in yellow catfish through PI3K signaling pathway
metabolism
knockdown studies of endogenous PI3K isoforms and clathrin heavy chain (CHC) mediated by small interfering RNA (siRNA) demonstrate that the class II PI3K PI3K-C2alpha and PI3K-C2beta, but not the class I or III PI3K, are required for pinocytosis, based on an evaluation of fluorescein-5-isothiocyanate (FITC)-dextran uptake in endothelial cells. Pinocytosis is partially dependent on both clathrin and dynamin, and both PI3K-C2alpha and PI3K-C2beta are required for clathrin-mediated, but not clathrin-nonmediated, FITC-dextran uptake at the step leading up to its delivery to early endosomes. PI3K-C2alpha and PI3K-C2beta play differential, indispensable roles in clathrin-mediated pinocytosis
physiological function
class II phosphoinositide 3-kinase C2beta regulates a novel signaling pathway involved in breast cancer progression. Isozyme PI3K-C2beta regulates breast cancer cell growth in vitro and in vivo, PI3K-C2beta expression in breast tissues is correlated with the proliferative status of the tumor. Analsis of the mechanism of the PI3K-C2beta-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2beta regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. PI3K-C2beta may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread. PI3K-C2beta regulates cyclin B1 expression through modulation of miR-449a, miR-449a levels are downregulated in primary human breast cancer samples, and cyclin B1/miR-449a expression through modulation of LEF1/beta catenin pathway in MDA-MB-231 cells. PI3K-C2beta regulates senescence via miR-449 regulation
physiological function
isozyme phosphatidylinositol 3-kinase class II alpha is required for transforming growth factor beta-induced Smad signaling in endothelial cells, but not in smooth muscle cells or epithelial cells. TGFbeta1-induced phosphorylation and nuclear translocation of Smad2/3 are dependent on class II PI3K-C2alpha. C2alpha is required for SARA-Smad2/3 complex formation
physiological function
isozyme PI3K-C2beta regulates mitogen-activated protein kinase kinase (MEK1/2) and extracellular signal-regulated kinase (ERK1/2) activation in prostate cancer (PCa) cells. MEK/ERK and isozyme PI3K-C2beta are required for PCa cell invasion but not proliferation. MEK/ERK and PI3K-C2beta are not required for PCa cell proliferation. PI3K-C2beta but not MEK/ERK regulates PCa cell migration as well as expression of the transcription factor Slug. PI3K-C2beta regulates FBS-induced PCa cell migration in a mechanism that does not appear to involve MEK/ERK activation
physiological function
phosphatidylinositol 3-kinase class 2 beta isoform, PI3KC2beta, contributes to neuroblastoma tumorigenesis. Activation of the PI3K target AKT is frequent in neuroblastoma and correlates with poor prognosis
physiological function
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PI3K-C2beta regulates the FceRI-stimulated activation of the KCa3.1 channel and the FceRI-induced Ca2+ influx and degranulation in BMMCs. PI3K-C2alpha regulates the FceRI-triggered degranulation by a mechanism different from that induced by PI3K-C2beta. PI3KC2alpha and PI3K-C2beta share different roles in the FceRI-regulated degranulation pathway
physiological function
PI3KC2alpha is important for mouse platelet function in vivo and plays an important role in regulating endothelial cell barrier function and vasculogenesis. Role for PI3KC2alpha in regulating the internal membrane reserve structure of megakaryocytes (demarcation membrane system) and platelets (open canalicular system) that results in dysregulated platelet adhesion under haemodynamic shear stress. Important role for PI3KC2alpha in regulating shear-dependent platelet adhesion via regulation of membrane structure, rather than acute signalling
physiological function
class II phosphoinositide 3-kinase alpha-isoform (PI3K-C2alpha) is involved in regulating KCl-induced vascular smooth muscle contraction. PI3K-C2alpha mediates part of sevoflurane (SEVO)- and isoflurane (ISO)-mediated vasodilation in rat aorta
physiological function
class II phosphoinositide 3-kinases PI3K-C2alpha and PI3K-C2beta differentially regulate clathrin-dependent pinocytosis in human vascular endothelial cells. Pinocytosis is partially dependent on both clathrin and dynamin, and both PI3K-C2alpha and PI3K-C2beta are required for clathrin-mediated, but not clathrin-nonmediated, FITC-dextran uptake at the step leading up to its delivery to early endosomes. PI3K-C2alpha and PI3K-C2beta play differential, indispensable roles in clathrin-mediated pinocytosis
physiological function
class II phosphoinositide 3-kinases PI3K-C2alpha and PI3K-C2beta differentially regulate clathrin-dependent pinocytosis in human vascular endothelial cells. Pinocytosis is partially dependent on both clathrin and dynamin, and both PI3K-C2alpha and PI3K-C2beta are required for clathrin-mediated, but not clathrin-nonmediated, FITC-dextran uptake at the step leading up to its delivery to early endosomes. PI3K-C2alpha and PI3K-C2beta play differential, indispensable roles in clathrin-mediated pinocytosis. Endogenous ITSN1 is required for the formation of actin patches and recruitment of PI3K-C2beta to the clathrin-coated structures. mCherry-C2beta overexpression stimulates pinocytosis through the mechanisms involving GFP-ITSN1-mediated recruitment of mCherry-C2beta
physiological function
importance of PI3KC2beta in ovarian cancer cell migration
physiological function
PI3KC2alpha has a role in glucose transport and secretion. Possible role of PI3KC2alpha in carcinogenesis, possible involvement of PI3KC2alpha in breast cancer development, and potential involvement of PI3KC2alpha in tumor angiogenesis favoring lung cancer and melanoma. Role for PI3KC2alpha in platelet function. PI3KC2alpha regulates a basal pool of PtdIns3P in platelets that may lead to impaired regulation of the platelet's cytoskeletal-membrane system
physiological function
PI3KC2beta plays an essential role in neuroblastoma development by mediating functions of ITSN1 and by stabilizing metylocytomatosis viral oncogene (MYCN), an oncogene found in 20% of neuroblastoma cases and a marker for poor prognosis. Correlation between PI3KC2beta expression levels and esophageal squamous-cell carcinoma (ESCC) metastasis. PI3KC2beta is involved in the regulation of cell invasion in PCa cells, partly by activation of MEK/ERK pathways and partly by regulation of cell migration through regulation of Slug protein. This protein is essential for epithelial-mesenchymal transition (EMT), a process which enables cells to gain migratory and invasive properties. PI3KC2beta has no influence on PCa cell proliferation. But it plays crucial roles in cell motility, migration, and invasion. PI3KC2beta is involved in the regulation of cell migration and invasion in different cancers. Implication of PI3KC2beta in metastasis has been demonstrated in breast, prostate, and ovarian cancers. The enzyme has a key role in lamellipodia formation in ovarian cancer SKOV3 cells, allowing for the increase in cell motility. A specific role for this enzyme in ovarian cancer cell motility and, as a consequence, in cancer metastasis. Importance of PI3KC2beta in ovarian cancer cell migration. Overexpression of PI3KC2beta has been also found to enhance migration of A-431 epidermoid carcinoma cells, HeLa and ovarian cancer cells, whereas overexpression of the negative PI3KC2beta is able to reduce this process. Possible mechanism of contribution of PI3KC2beta in cancer cell migration and metastasis included PIK3C2B is regulated by miR-515-5p, which plays a role in the control of cancer cell migration and metastasis. Overexpression of miR-515-5p downregulates PIK3C2B, among others, binding directly to its 3'-UTR region
physiological function
PIK3C2G, the gene encoding PI3KC2gamma, acts mainly as a tumor suppressor gene. Low PI3KC2gamma expression influences colorectal cancer (CRC) development, with low copy number of PIK3C2G associated with a 2.5fold increase in the risk of death
additional information
PI3KC2beta catalytic site structure, overview
additional information
PI3KC2beta catalytic site structure, overview
additional information
PI3KC2beta catalytic site structure, overview