ID:P3C2A_HUMAN DESCRIPTION: RecName: Full=Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha; Short=PI3K-C2-alpha; Short=PtdIns-3-kinase C2 subunit alpha; EC=2.7.1.154; AltName: Full=Phosphoinositide 3-kinase-C2-alpha; FUNCTION: Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin- mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin- independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function. CATALYTIC ACTIVITY: ATP + 1-phosphatidyl-1D-myo-inositol 4- phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate. COFACTOR: Calcium or magnesium. Manganese cannot be used. ENZYME REGULATION: Activated by insulin (By similarity). Only slightly inhibited by wortmannin and LY294002. Activated by clathrin. BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=122 uM for PtdIns (in the absence of phosphatidylserine); KM=64 uM for PtdIns (in the presence of phosphatidylserine); KM=25 uM for PtdIns4P (in the presence of phosphatidylserine); KM=15 uM for ATP (with PtdIns as substrate) (in the absence of phosphatidylserine); KM=32 uM for ATP (with PtdIns as substrate) (in the presence of phosphatidylserine); KM=54 uM for ATP (with PtdIns4P as substrate) (in the presence of phosphatidylserine); Vmax=990 pmol/min/mg enzyme with PtdIns as substrate (in the absence of phosphatidylserine); Vmax=200 pmol/min/mg enzyme with PtdIns as substrate (in the presence of phosphatidylserine); Vmax=240 pmol/min/mg enzyme with PtdIns4P as substrate (in the presence of phosphatidylserine); Vmax=6800 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in the absence of phosphatidylserine); Vmax=805 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in the presence of phosphatidylserine); Vmax=880 pmol/min/mg enzyme toward ATP with PtdIns4P as substrate (in the presence of phosphatidylserine); Note=In the absence of the carrier phosphatidylserine, enzymatic kinetics toward PtdIns4P are non-linear; SUBUNIT: Part of a complex with ERBB2 and EGFR. Interacts with clathrin trimers. SUBCELLULAR LOCATION: Cell membrane. Golgi apparatus. Cytoplasmic vesicle, clathrin-coated vesicle. Nucleus. Cytoplasm. Note=According to PubMed:10766823 and PubMed:11239472, it is found in the cell membrane, the Golgi apparatus and in clathrin-coated vesicles. According to PubMed:17038310 it inserts preferentially into membranes containing PtdIns(4,5)P2. According to PubMed:11606566, it is nuclear and cytoplasmic. Associated with RNA-containing structures. According to PubMed:14563213, it is mainly cytoplasmic. TISSUE SPECIFICITY: Expressed in columnar and transitional epithelia, mononuclear cells, smooth muscle cells, and endothelial cells lining capillaries and small venules (at protein level). Ubiquitously expressed, with highest levels in heart, placenta and ovary, and lowest levels in the kidney. Detected at low levels in islets of Langerhans from type 2 diabetes mellitus individuals. PTM: Phosphorylated upon insulin stimulation; which may lead to enzyme activation (By similarity). Phosphorylated on Ser-259 during mitosis and upon UV irradiation; which does not change enzymatic activity but leads to proteasomal degradation. Ser-259 phosphorylation may be mediated by CDK1 or JNK, depending on the physiological state of the cell. SIMILARITY: Belongs to the PI3/PI4-kinase family. SIMILARITY: Contains 1 C2 domain. SIMILARITY: Contains 1 C2 PI3K-type domain. SIMILARITY: Contains 1 PI3K-RBD domain. SIMILARITY: Contains 1 PI3K/PI4K domain. SIMILARITY: Contains 1 PIK helical domain. SIMILARITY: Contains 1 PX (phox homology) domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O00443
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Protein O00443 (Reactome details) participates in the following event(s):
R-HSA-8868071 Clathrin recruits PIK3C2A R-HSA-8867754 F- and N- BAR domain proteins bind the clathrin-coated pit R-HSA-421833 Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture R-HSA-421836 trans-Golgi Network Derived Vesicle Uncoating R-HSA-421831 trans-Golgi Network Coat Assembly R-HSA-421835 trans-Golgi Network Vesicle Scission R-HSA-1676206 PI4P is phosphorylated to PI(3,4)P2 by PIK3C2A at the early endosome membrane R-HSA-8868072 Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2 R-HSA-1675939 PI is phosphorylated to PI3P by PIK3C2A/3 at the early endosome membrane R-HSA-1675961 PI is phosphorylated to PI3P by PIK3C2A/3 at the Golgi membrane R-HSA-1676024 PI is phosphorylated to PI3P by PIK3C2A/3 at the late endosome membrane R-HSA-1676109 PI4P is phosphorylated to PI(3,4)P2 by PI3K3C[2] at the plasma membrane R-HSA-1675928 PI4P is phosphorylated to PI(3,4)P2 by PIK3C2A/G at the Golgi membrane R-HSA-8856828 Clathrin-mediated endocytosis R-HSA-432722 Golgi Associated Vesicle Biogenesis R-HSA-199991 Membrane Trafficking R-HSA-421837 Clathrin derived vesicle budding R-HSA-1660516 Synthesis of PIPs at the early endosome membrane R-HSA-5653656 Vesicle-mediated transport R-HSA-199992 trans-Golgi Network Vesicle Budding R-HSA-1660514 Synthesis of PIPs at the Golgi membrane R-HSA-1660517 Synthesis of PIPs at the late endosome membrane R-HSA-1660499 Synthesis of PIPs at the plasma membrane R-HSA-1483255 PI Metabolism R-HSA-1483257 Phospholipid metabolism R-HSA-556833 Metabolism of lipids R-HSA-1430728 Metabolism
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Common Gene Haplotype Alleles 
