ID KPCA_RABIT Reviewed; 672 AA. AC P10102; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 02-SEP-2026, entry version 199. DE RecName: Full=Protein kinase C alpha type; DE Short=PKC-A; DE Short=PKC-alpha; DE EC=2.7.11.13 {ECO:0000250|UniProtKB:P17252}; GN Name=PRKCA; OS Oryctolagus cuniculus (Rabbit). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus. OX NCBI_TaxID=9986; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RX PubMed=3808073; DOI=10.1038/325161a0; RA Ohno S., Kawasaki H., Imajoh S., Suzuki K., Inagaki M., Yokokura H., RA Sakoh T., Hidaka H.; RT "Tissue-specific expression of three distinct types of rabbit protein RT kinase C."; RL Nature 325:161-166(1987). RN [2] RP REVIEW. RX PubMed=3045562; DOI=10.1038/334661a0; RA Nishizuka Y.; RT "The molecular heterogeneity of protein kinase C and its implications for RT cellular regulation."; RL Nature 334:661-665(1988). CC -!- FUNCTION: Calcium-activated, phospholipid- and diacylglycerol (DAG)- CC dependent serine/threonine-protein kinase that is involved in positive CC and negative regulation of cell proliferation, apoptosis, CC differentiation, migration and adhesion, cardiac hypertrophy, CC angiogenesis, platelet function and inflammation, by directly CC phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or CC activating signaling cascades involving MAPK1/3 (ERK1/2) and RAP1GAP. CC Depending on the cell type, is involved in cell proliferation and cell CC growth arrest by positive and negative regulation of the cell cycle. CC Can promote cell growth by phosphorylating and activating RAF1, which CC mediates the activation of the MAPK/ERK signaling cascade, and/or by CC up-regulating CDKN1A, which facilitates active cyclin-dependent kinase CC (CDK) complex formation. In cells stimulated by the phorbol ester PMA, CC can trigger a cell cycle arrest program which is associated with the CC accumulation of the hyper-phosphorylated growth-suppressive form of RB1 CC and induction of the CDK inhibitors CDKN1A and CDKN1B. Depending on the CC cell type, exhibits anti-apoptotic function and protects cells from CC apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, or CC mediates anti-apoptotic action by phosphorylating BCL2. During CC macrophage differentiation induced by macrophage colony-stimulating CC factor (CSF1), is translocated to the nucleus and is associated with CC macrophage development. After wounding, translocates from focal CC contacts to lamellipodia and participates in the modulation of CC desmosomal adhesion. Plays a role in cell motility by phosphorylating CC CSPG4, which induces association of CSPG4 with extensive lamellipodia CC at the cell periphery and polarization of the cell accompanied by CC increases in cell motility. During chemokine-induced CD4(+) T cell CC migration, phosphorylates CDC42-guanine exchange factor DOCK8 resulting CC in its dissociation from LRCH1 and the activation of GTPase CDC42. CC Negatively regulates myocardial contractility and positively regulates CC angiogenesis, platelet aggregation and thrombus formation in arteries. CC Mediates hypertrophic growth of neonatal cardiomyocytes, in part CC through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA CC treatment, is required to induce cardiomyocyte hypertrophy up to heart CC failure and death, by increasing protein synthesis, protein-DNA ratio CC and cell surface area. Regulates cardiomyocyte function by CC phosphorylating cardiac troponin T (TNNT2/CTNT), which induces CC significant reduction in actomyosin ATPase activity, myofilament CC calcium sensitivity and myocardial contractility. In angiogenesis, is CC required for full endothelial cell migration, adhesion to vitronectin CC (VTN), and vascular endothelial growth factor A (VEGFA)-dependent CC regulation of kinase activation and vascular tube formation. Involved CC in the stabilization of VEGFA mRNA at post-transcriptional level and CC mediates VEGFA-induced cell proliferation. In the regulation of CC calcium-induced platelet aggregation, mediates signals from the CC CD36/GP4 receptor for granule release, and activates the integrin CC heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. CC During response to lipopolysaccharides (LPS), may regulate selective CC LPS-induced macrophage functions involved in host defense and CC inflammation. But in some inflammatory responses, may negatively CC regulate NF-kappa-B-induced genes, through IL1A-dependent induction of CC NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O- CC tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which CC modulates EIF4G1 binding to MKNK1 and may be involved in the regulation CC of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of CC KIT activity. Phosphorylates ATF2 which promotes cooperation between CC ATF2 and JUN, activating transcription. Phosphorylates SOCS2 at 'Ser- CC 52' facilitating its ubiquitination and proteasomal degradation (By CC similarity). Phosphorylates KLHL3 in response to angiotensin II CC signaling, decreasing the interaction between KLHL3 and WNK4 (By CC similarity). Phosphorylates and activates LRRK1, which phosphorylates CC RAB proteins involved in intracellular trafficking (By similarity). CC Acts as a regulator of dopamine signaling by mediating constitutive CC phosphorylation of dopamine receptor DRD1, inhibiting G protein-coupled CC receptor signaling (By similarity). {ECO:0000250|UniProtKB:P17252, CC ECO:0000250|UniProtKB:P20444}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.13; CC Evidence={ECO:0000250|UniProtKB:P17252}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.13; CC Evidence={ECO:0000250|UniProtKB:P17252}; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000255|PROSITE- CC ProRule:PRU00041}; CC Note=Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 CC domain. {ECO:0000250|UniProtKB:P05696}; CC -!- ACTIVITY REGULATION: Classical (or conventional) PKCs (PRKCA, PRKCB and CC PRKCG) are activated by calcium and diacylglycerol (DAG) in the CC presence of phosphatidylserine. Three specific sites; Thr-497 CC (activation loop of the kinase domain), Thr-638 (turn motif) and Ser- CC 657 (hydrophobic region), need to be phosphorylated for its full CC activation. CC -!- SUBUNIT: Interacts with ADAP1/CENTA1, CSPG4 and PRKCABP. Binds to CC CAVIN2 in the presence of phosphatidylserine. Interacts with PICK1 (via CC PDZ domain). Interacts with TRIM41. Recruited in a circadian manner CC into a nuclear complex which also includes BMAL1 and RACK1. Interacts CC with PARD3 (By similarity). Interacts with SOCS2 (By similarity). CC {ECO:0000250|UniProtKB:P05696, ECO:0000250|UniProtKB:P17252, CC ECO:0000250|UniProtKB:P20444}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane CC {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. Mitochondrion CC membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. CC Nucleus {ECO:0000250}. CC -!- PTM: In response to growth factors, phosphorylated at Thr-631 and Ser- CC 657 by the mTORC2 complex, promoting autophosphorylation and activation CC of PRKCE. {ECO:0000250|UniProtKB:P17252}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr CC protein kinase family. PKC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X04796; CAA28483.1; -; mRNA. DR PIR; C26037; KIRBC. DR RefSeq; NP_001095194.1; NM_001101724.1. DR AlphaFoldDB; P10102; -. DR SMR; P10102; -. DR FunCoup; P10102; 129. DR STRING; 9986.ENSOCUP00000025402; -. DR SwissPalm; P10102; -. DR PaxDb; 9986-ENSOCUP00000025402; -. DR GeneID; 100037720; -. DR KEGG; ocu:100037720; -. DR CTD; 5578; -. DR eggNOG; KOG0696; Eukaryota. DR InParanoid; P10102; -. DR OrthoDB; 63267at2759; -. DR BRENDA; 2.7.11.13; 1749. DR Proteomes; UP000001811; Unplaced. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0004698; F:calcium,diacylglycerol-dependent serine/threonine kinase activity; ISS:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; ISS:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB. DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB. DR GO; GO:0045785; P:positive regulation of cell adhesion; ISS:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB. DR GO; GO:2000707; P:positive regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; ISS:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0045651; P:positive regulation of macrophage differentiation; ISS:UniProtKB. DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:0090330; P:regulation of platelet aggregation; ISS:UniProtKB. DR GO; GO:1903530; P:regulation of secretion by cell; IEA:UniProtKB-ARBA. DR CDD; cd20833; C1_cPKC_rpt1; 1. DR CDD; cd20836; C1_cPKC_rpt2; 1. DR CDD; cd04026; C2_PKC_alpha_gamma; 1. DR CDD; cd05615; STKc_cPKC_alpha; 1. DR FunFam; 2.60.40.150:FF:000012; Kinase C alpha type; 1. DR FunFam; 1.10.510.10:FF:000023; Protein kinase C; 1. DR FunFam; 3.30.200.20:FF:000080; Protein kinase C; 1. DR FunFam; 3.30.200.20:FF:000103; Protein kinase C; 1. DR FunFam; 3.30.60.20:FF:000006; Protein kinase C; 1. DR FunFam; 3.30.60.20:FF:000031; Protein kinase C alpha; 1. DR Gene3D; 3.30.60.20; -; 2. DR Gene3D; 2.60.40.150; C2 domain; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 2. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR000961; AGC-kinase_C. DR InterPro; IPR046349; C1-like_sf. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR034663; cPKC_alpha. DR InterPro; IPR020454; DAG/PE-bd. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR002219; PKC_DAG/PE. DR InterPro; IPR017892; Pkinase_C. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR014375; Protein_kinase_C_a/b/g. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24351; RIBOSOMAL PROTEIN S6 KINASE; 1. DR Pfam; PF00130; C1_1; 2. DR Pfam; PF00168; C2; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF00433; Pkinase_C; 1. DR PIRSF; PIRSF000550; PKC_alpha; 1. DR PRINTS; PR00360; C2DOMAIN. DR PRINTS; PR00008; DAGPEDOMAIN. DR SMART; SM00109; C1; 2. DR SMART; SM00239; C2; 1. DR SMART; SM00133; S_TK_X; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 1. DR SUPFAM; SSF57889; Cysteine-rich domain; 2. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS51285; AGC_KINASE_CTER; 1. DR PROSITE; PS50004; C2; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS00479; ZF_DAG_PE_1; 2. DR PROSITE; PS50081; ZF_DAG_PE_2; 2. PE 2: Evidence at transcript level; KW Acetylation; Angiogenesis; Apoptosis; ATP-binding; Calcium; Cell adhesion; KW Cell membrane; Cytoplasm; Kinase; Membrane; Metal-binding; Mitochondrion; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000250|UniProtKB:P17252" FT CHAIN 2..672 FT /note="Protein kinase C alpha type" FT /id="PRO_0000055681" FT DOMAIN 158..275 FT /note="C2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 339..597 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 598..668 FT /note="AGC-kinase C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618" FT ZN_FING 36..86 FT /note="Phorbol-ester/DAG-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226" FT ZN_FING 101..151 FT /note="Phorbol-ester/DAG-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226" FT ACT_SITE 463 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 186 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 187 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 187 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 193 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 195 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- FT inositol-4,5-bisphosphate)" FT /ligand_id="ChEBI:CHEBI:58456" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 245 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- FT inositol-4,5-bisphosphate)" FT /ligand_id="ChEBI:CHEBI:58456" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 246 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 246 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 247 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 248 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 248 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 248 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 252 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 254 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 254 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P05696" FT BINDING 345..353 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 368 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 10 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 226 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 319 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P05696" FT MOD_RES 494 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P04409" FT MOD_RES 495 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P04409" FT MOD_RES 497 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000250|UniProtKB:P04409" FT MOD_RES 501 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P05771" FT MOD_RES 628 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 631 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P20444" FT MOD_RES 638 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 651 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17252" FT MOD_RES 657 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P05771" FT MOD_RES 658 FT /note="Phosphotyrosine; by SYK" FT /evidence="ECO:0000250|UniProtKB:P20444" SQ SEQUENCE 672 AA; 76782 MW; 3D311367D3577A77 CRC64; MADVFPANDS TASQDVANRF ARKGALRQKN VHEVKDHKFI ARFFKQPTFC SHCTDFIWGF GKQGFQCQVC CFVVHKRCHE FVTFSCPGAD KGPDTDDPRS KHKFKIHTYG SPTFCDHCGS LLYGLIHQGM KCDTCDMNVH KQCVINVPSL CGMDHTEKRG RIYLKAEVTD EKLHVTVRDA KNLIPMDPNG LSDPYVKLKL IPDPKNESKQ KTKTIRSTLN PQWNESFTFK LKPSDKDRRL SVEIWDWDRT TRNDFMGSLS FGVSELMKMP ASGWYKLLNQ EEGEYYNVPI PEGDEDGNVE LRQKFEKAKL GPAGNKVISP SEDRKQPSNN LDRVKLTDFN FLMVLGKGSF GKVMLADRKG TEELYAIKIL KKDVVIQDDD VECTMVEKRV LALMDKPPFL TQLHSCFQTV DRLYFVMEYV NGGDLMYHIQ QVGKFKEPQA VFYAAEISIG LFFLHKRGII YRDLKLDNVM LDSEGHIKIA DFGMCKEHMM DGVTTRTFCG TPDYIAPEII AYQPYGKSVD WWAYGVLLYE MLAGQPPFDG EDEDELFQSI MEHNVSYPKS LSKEAVSICK GLMTKHPAKR LGCGPEGERD VREHAFFRRI DWEKLENREI QPPFKPKVCG KGAENFDKFF TRGQPVVTPP DQLVIANIDQ SDFEGFSYVN PQFVHPILQS SV //