P04409 (KPCA_BOVIN) Reviewed, UniProtKB/Swiss-Prot
Last modified May 29, 2013. Version 138. History...
Names and origin
|Protein names||Recommended name:|
Protein kinase C alpha type
|Organism||Bos taurus (Bovine) [Reference proteome]|
|Taxonomic identifier||9913 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos|
|Sequence length||672 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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, 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. Depending on the cell type, is 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 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. Depending on the cell type, exhibits anti-apoptotic function and protects cells from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, or 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. 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 By similarity.
ATP + a protein = ADP + a phosphoprotein.
Binds 3 calcium ions per subunit. The ions are bound to the C2 domain By similarity.
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.
Interacts with ADAP1/CENTA1, CSPG4 and PRKCABP. Binds to SDPR in the presence of phosphatidylserine By similarity. Interacts with PICK1 (via PDZ domain) By similarity. Interacts with TRIM41 By similarity. Recruited in a circadian manner into a nuclear complex which also includes BMAL1 and GNB2L1/RACK1 By similarity.
Contains 1 AGC-kinase C-terminal domain.
Contains 1 C2 domain.
Contains 2 phorbol-ester/DAG-type zinc fingers.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 672||671||Protein kinase C alpha type||PRO_0000055678|
|Domain||172 – 260||89||C2|
|Domain||339 – 597||259||Protein kinase|
|Domain||598 – 668||71||AGC-kinase C-terminal|
|Zinc finger||36 – 86||51||Phorbol-ester/DAG-type 1|
|Zinc finger||101 – 151||51||Phorbol-ester/DAG-type 2|
|Nucleotide binding||345 – 353||9||ATP By similarity|
|Active site||463||1||Proton acceptor By similarity|
|Metal binding||186||1||Calcium 1; via carbonyl oxygen By similarity|
|Metal binding||187||1||Calcium 1 By similarity|
|Metal binding||187||1||Calcium 2 By similarity|
|Metal binding||193||1||Calcium 2 By similarity|
|Metal binding||246||1||Calcium 1 By similarity|
|Metal binding||246||1||Calcium 2 By similarity|
|Metal binding||247||1||Calcium 2; via carbonyl oxygen By similarity|
|Metal binding||248||1||Calcium 1 By similarity|
|Metal binding||248||1||Calcium 2 By similarity|
|Metal binding||248||1||Calcium 3 By similarity|
|Metal binding||252||1||Calcium 3; via carbonyl oxygen By similarity|
|Metal binding||254||1||Calcium 1 By similarity|
|Metal binding||254||1||Calcium 3 By similarity|
|Binding site||195||1||Inositol phosphate group By similarity|
|Binding site||245||1||Inositol phosphate group By similarity|
|Binding site||368||1||ATP By similarity|
Amino acid modifications
|Modified residue||226||1||Phosphoserine By similarity|
|Modified residue||250||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||319||1||Phosphoserine By similarity|
|Modified residue||494||1||Phosphothreonine Probable|
|Modified residue||495||1||Phosphothreonine Probable|
|Modified residue||497||1||Phosphothreonine; by PDPK1 Probable|
|Modified residue||628||1||N6-acetyllysine By similarity|
|Modified residue||631||1||Phosphothreonine; by autocatalysis Potential|
|Modified residue||638||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||651||1||Phosphoserine By similarity|
|Modified residue||657||1||Phosphoserine Ref.4|
|Modified residue||658||1||Phosphotyrosine; by SYK By similarity|
|Mutagenesis||494||1||T → A: Abolishes phosphorylation and catalytic activity; when associated with A-495 and A-497. Ref.3|
|Mutagenesis||495||1||T → A: Abolishes phosphorylation and catalytic activity; when associated with A-494 and A-497. Ref.3|
|Mutagenesis||497||1||T → A: Abolishes phosphorylation and catalytic activity; when associated with A-494 and A-495. Ref.3|
|||"The complete primary structure of protein kinase C -- the major phorbol ester receptor."|
Parker P.J., Coussens L., Totty N., Rhee L., Young S., Chen E., Stabel S., Waterfield M.D., Ullrich A.
Science 233:853-859(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"The molecular heterogeneity of protein kinase C and its implications for cellular regulation."|
Nature 334:661-665(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|||"Identification of the phosphorylated region responsible for the permissive activation of protein kinase C."|
Cazaubon S.M., Parker P.J.
J. Biol. Chem. 268:17559-17563(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF THR-494; THR-495 AND THR-497, PHOSPHORYLATION AT THR-494; THR-495 AND THR-497.
|||"Phosphorylation of protein kinase C-alpha on serine 657 controls the accumulation of active enzyme and contributes to its phosphatase-resistant state."|
Bornancin F., Parker P.J.
J. Biol. Chem. 272:3544-3549(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-657.
|M13973 mRNA. Translation: AAA30706.1.|
|PIR||KIBOC. A00621. |
|RefSeq||NP_776860.1. NM_174435.1. |
3D structure databases
|SMR||P04409. Positions 37-292, 336-666. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
Enzyme and pathway databases
|BRENDA||22.214.171.124. 908. |
|Reactome||REACT_114534. Signal Transduction. |
Family and domain databases
|InterPro||IPR000961. AGC-kinase_C. |
|Pfam||PF00130. C1_1. 2 hits. |
PF00168. C2. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
|PIRSF||PIRSF000550. PKC_alpha. 1 hit. |
|PRINTS||PR00360. C2DOMAIN. |
|SMART||SM00109. C1. 2 hits. |
SM00239. C2. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF49562. C2_CaLB. 1 hit. |
SSF56112. Kinase_like. 1 hit.
|PROSITE||PS51285. AGC_KINASE_CTER. 1 hit. |
PS50004. C2. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 2 hits.
PS50081. ZF_DAG_PE_2. 2 hits.
|Accession||Primary (citable) accession number: P04409|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families