Short name=PKC-A
Short name=PKC-alpha
EC=2.7.11.13
Gene names
Name: PRKCA
Synonyms: PKCA, PRKACA
Function
カルシウムで活性化されるリン脂質とジアシルグリセロール依存性のセリン・トレオニンキナーゼで、細胞の増殖、アポトーシス、分化、遊走、接着、腫瘍形成、心肥大、血管新生、血小板機能、炎症に直接的なリン酸化反応のターゲット（RAF1, BCL2, CSPG4, TNNT2/CTNTなど）を介して、またはMAPKとRAP1GAPのシグナルカスケードの活性化を介して関与する。
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP.
細胞周期を調節することで細胞の増殖や成長の停止に関与する。細胞の成長をMAPK/ERKシグナルカスケードの活性化を介するRAF1のリン酸化、および、グリオーマ細胞でサイクリン依存性キナーゼ複合体の活性化を担うCDKN1Aのアップレギュレーションによって促す。
Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells.
ホルボールエステルによって刺激された小腸細胞では、高度にリン酸化されたRB1の蓄積とCDK阻害作用のあるCDKN1AとCDKN1Bの誘導により細胞周期停止のきっかけとなる。
In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B.
グリオーマ細胞ではp53/TP53の介在により活性化されるIGFBP3の抑制により、また白血病細胞ではBCL2のリン酸化により抗アポトーシス活性を示す。
Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2.
マクロファージコロニー刺激因子によるマクロファージの分化に際して、核内に移動し、マクロファージの分化に関与する。
During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF-kappa-B-induced genes, through IL1A-dependent induction of NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.16 Ref.17 Ref.18 Ref.20 Ref.26 Ref.34
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Cofactor
Binds 3 calcium ions per subunit. The ions are bound to the C2 domain By similarity.
Enzyme regulation
Classical (or conventional) PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. Three specific sites; Thr-497 (activation loop of the kinase domain), Thr-638 (turn motif) and Ser-657 (hydrophobic region), need to be phosphorylated for its full activation.
Subunit structure
Recruited in a circadian manner into a nuclear complex which also includes BMAL1 and GNB2L1/RACK1 By similarity. Interacts with ADAP1/CENTA1, CSPG4 and PRKCABP. Binds to SDPR in the presence of phosphatidylserine. Interacts with PICK1 (via PDZ domain). Interacts with TRIM41. Ref.15 Ref.19 Ref.20 Ref.25
Subcellular location
Cytoplasm. Cell membrane; Peripheral membrane protein. Mitochondrion membrane; Peripheral membrane protein Probable. Nucleus Ref.9.
Sequence similarities
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily.
Contains 1 AGC-kinase C-terminal domain.
Contains 1 C2 domain.
Contains 2 phorbol-ester/DAG-type zinc fingers.
Contains 1 protein kinase domain.
