8u37

Structural highlights

Function

KPCA_HUMAN 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. 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. 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. 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. 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.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]}

References

1. ↑ Ruvolo PP, Deng X, Carr BK, May WS. A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem. 1998 Sep 25;273(39):25436-42. PMID:9738012
2. ↑ St-Denis A, Chano F, Tremblay P, St-Pierre Y, Descoteaux A. Protein kinase C-alpha modulates lipopolysaccharide-induced functions in a murine macrophage cell line. J Biol Chem. 1998 Dec 4;273(49):32787-92. PMID:9830023
3. ↑ Han Y, Meng T, Murray NR, Fields AP, Brasier AR. Interleukin-1-induced nuclear factor-kappaB-IkappaBalpha autoregulatory feedback loop in hepatocytes. A role for protein kinase calpha in post-transcriptional regulation of ikappabalpha resynthesis. J Biol Chem. 1999 Jan 8;274(2):939-47. PMID:9873035
4. ↑ Shen L, Dean NM, Glazer RI. Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide. Mol Pharmacol. 1999 Feb;55(2):396-402. PMID:9927633
5. ↑ Besson A, Yong VW. Involvement of p21(Waf1/Cip1) in protein kinase C alpha-induced cell cycle progression. Mol Cell Biol. 2000 Jul;20(13):4580-90. PMID:10848585
6. ↑ Wang A, Nomura M, Patan S, Ware JA. Inhibition of protein kinase Calpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo. Circ Res. 2002 Mar 22;90(5):609-16. PMID:11909826
7. ↑ Tabuchi A, Yoshioka A, Higashi T, Shirakawa R, Nishioka H, Kita T, Horiuchi H. Direct demonstration of involvement of protein kinase Calpha in the Ca2+-induced platelet aggregation. J Biol Chem. 2003 Jul 18;278(29):26374-9. Epub 2003 Apr 30. PMID:12724315 doi:http://dx.doi.org/10.1074/jbc.M212407200
8. ↑ Sumandea MP, Pyle WG, Kobayashi T, de Tombe PP, Solaro RJ. Identification of a functionally critical protein kinase C phosphorylation residue of cardiac troponin T. J Biol Chem. 2003 Sep 12;278(37):35135-44. Epub 2003 Jun 28. PMID:12832403 doi:http://dx.doi.org/10.1074/jbc.M306325200
9. ↑ Ronnstrand L. Signal transduction via the stem cell factor receptor/c-Kit. Cell Mol Life Sci. 2004 Oct;61(19-20):2535-48. PMID:15526160 doi:http://dx.doi.org/10.1007/s00018-004-4189-6
10. ↑ Makagiansar IT, Williams S, Dahlin-Huppe K, Fukushi J, Mustelin T, Stallcup WB. Phosphorylation of NG2 proteoglycan by protein kinase C-alpha regulates polarized membrane distribution and cell motility. J Biol Chem. 2004 Dec 31;279(53):55262-70. Epub 2004 Oct 25. PMID:15504744 doi:http://dx.doi.org/M411045200
11. ↑ Xu H, Czerwinski P, Hortmann M, Sohn HY, Forstermann U, Li H. Protein kinase C alpha promotes angiogenic activity of human endothelial cells via induction of vascular endothelial growth factor. Cardiovasc Res. 2008 May 1;78(2):349-55. Epub 2007 Dec 4. PMID:18056764 doi:http://dx.doi.org/10.1093/cvr/cvm085
12. ↑ Dobrikov M, Dobrikova E, Shveygert M, Gromeier M. Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1. Mol Cell Biol. 2011 Jul;31(14):2947-59. doi: 10.1128/MCB.05589-11. Epub 2011 May , 16. PMID:21576361 doi:http://dx.doi.org/10.1128/MCB.05589-11
13. ↑ Visser M, Papillon JPN, Luzzio M, LaMarche MJ, Fan J, Michael W, Wang D, Zhang A, Straub C, Mathieu S, Kato M, Palermo M, Chen C, Ramsey T, Joud C, Barrett R, Vattay A, Guo R, Bric A, Chung F, Liang G, Romanowski MJ, Lam J, Thohan S, Atassi F, Wylie A, Cooke VG. Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma. J Med Chem. 2024 Jan 10. PMID:38198520 doi:10.1021/acs.jmedchem.3c02002