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P20444 (KPCA_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 152. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Protein kinase C alpha type

Short name=PKC-A
Short name=PKC-alpha
EC=2.7.11.13
Gene names
Name:Prkca
Synonyms:Pkca
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length672 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 cascades 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. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. Ref.3 Ref.5 Ref.8

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

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. Ref.4 Ref.9

Subcellular location

Cytoplasm. Cell membrane; Peripheral membrane protein. Mitochondrion membrane; Peripheral membrane protein Probable. Nucleus. Note: Translocated to the cell periphery upon tetradecanoyl phorbol acetate (TPA) treatment. Ref.6 Ref.9

Involvement in disease

Expression of the mutant form UV25 causes malignant transformation of cells.

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.

Ontologies

Keywords
   Biological processAngiogenesis
Apoptosis
Cell adhesion
   Cellular componentCell membrane
Cytoplasm
Membrane
Mitochondrion
Nucleus
   Coding sequence diversityPolymorphism
   DomainRepeat
Zinc-finger
   LigandATP-binding
Calcium
Metal-binding
Nucleotide-binding
Zinc
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

cell adhesion

Inferred from electronic annotation. Source: UniProtKB-KW

cellular calcium ion homeostasis

Inferred from mutant phenotype PubMed 14966518. Source: MGI

cellular response to carbohydrate stimulus

Inferred from direct assay PubMed 16585392. Source: MGI

chondrocyte differentiation

Inferred from direct assay PubMed 17644814. Source: MGI

inactivation of MAPK activity

Inferred from mutant phenotype PubMed 11923480. Source: MGI

induction of positive chemotaxis

Inferred from mutant phenotype PubMed 12928424. Source: MGI

intrinsic apoptotic signaling pathway

Inferred from mutant phenotype PubMed 12928424. Source: MGI

negative regulation of cell proliferation

Inferred from genetic interaction PubMed 17956267. Source: MGI

negative regulation of glial cell apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of glucose import

Inferred from mutant phenotype PubMed 11923480. Source: MGI

negative regulation of insulin receptor signaling pathway

Inferred from mutant phenotype PubMed 11923480. Source: MGI

negative regulation of protein kinase activity

Inferred from mutant phenotype PubMed 11923480. Source: MGI

negative regulation of protein phosphorylation

Inferred from mutant phenotype PubMed 14966518. Source: MGI

neutrophil chemotaxis

Inferred from mutant phenotype PubMed 12928424. Source: MGI

peptidyl-serine autophosphorylation

Inferred from direct assay PubMed 16814779. Source: MGI

positive regulation of ERK1 and ERK2 cascade

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of angiogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cardiac muscle hypertrophy

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell adhesion

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of dense core granule biogenesis

Inferred from mutant phenotype Ref.8. Source: UniProtKB

positive regulation of endothelial cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of endothelial cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of inflammatory response

Inferred from mutant phenotype PubMed 12928424. Source: MGI

positive regulation of lipopolysaccharide-mediated signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of macrophage differentiation

Inferred from mutant phenotype Ref.5. Source: UniProtKB

positive regulation of mitotic cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein phosphorylation

Inferred from mutant phenotype PubMed 14966518. Source: MGI

protein phosphorylation

Inferred from direct assay PubMed 12618484PubMed 7741753. Source: MGI

regulation of muscle contraction

Inferred from mutant phenotype PubMed 14966518. Source: MGI

regulation of peptidyl-tyrosine phosphorylation

Inferred from mutant phenotype PubMed 11940581. Source: MGI

regulation of platelet aggregation

Inferred from mutant phenotype Ref.8. Source: UniProtKB

regulation of the force of heart contraction

Inferred from mutant phenotype PubMed 14966518. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 10882525PubMed 12826667PubMed 12928424PubMed 14613966PubMed 15590069. Source: MGI

dendrite

Inferred from direct assay PubMed 12115694. Source: MGI

mitochondrial membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrion

Inferred from direct assay PubMed 12826667. Source: MGI

neuronal cell body

Inferred from direct assay PubMed 12115694. Source: MGI

nucleus

Inferred from direct assay PubMed 10882525PubMed 14613966PubMed 15590069. Source: MGI

perinuclear region of cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

photoreceptor outer segment

Inferred from direct assay PubMed 10813773. Source: MGI

plasma membrane

Inferred from direct assay PubMed 10882525. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

calcium-dependent protein kinase C activity

Inferred from direct assay PubMed 10879655PubMed 7741753. Source: MGI

protein kinase C activity

Inferred from direct assay PubMed 12618484PubMed 12970181. Source: MGI

protein serine/threonine kinase activity

Inferred from direct assay PubMed 14966518. Source: MGI

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ClockO087853EBI-6976815,EBI-79859

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 672671Protein kinase C alpha type
PRO_0000055680

Regions

Domain172 – 26089C2
Domain339 – 597259Protein kinase
Domain598 – 66871AGC-kinase C-terminal
Zinc finger36 – 8651Phorbol-ester/DAG-type 1
Zinc finger101 – 15151Phorbol-ester/DAG-type 2
Nucleotide binding345 – 3539ATP By similarity

Sites

Active site4631Proton acceptor By similarity
Metal binding1861Calcium 1; via carbonyl oxygen By similarity
Metal binding1871Calcium 1 By similarity
Metal binding1871Calcium 2 By similarity
Metal binding1931Calcium 2 By similarity
Metal binding2461Calcium 1 By similarity
Metal binding2461Calcium 2 By similarity
Metal binding2471Calcium 2; via carbonyl oxygen By similarity
Metal binding2481Calcium 1 By similarity
Metal binding2481Calcium 2 By similarity
Metal binding2481Calcium 3 By similarity
Metal binding2521Calcium 3; via carbonyl oxygen By similarity
Metal binding2541Calcium 1 By similarity
Metal binding2541Calcium 3 By similarity
Binding site1951Inositol phosphate group By similarity
Binding site2451Inositol phosphate group By similarity
Binding site3681ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue2261Phosphoserine By similarity
Modified residue2501Phosphothreonine; by autocatalysis By similarity
Modified residue4971Phosphothreonine; by PDPK1 By similarity
Modified residue6281N6-acetyllysine By similarity
Modified residue6311Phosphothreonine; by autocatalysis Potential
Modified residue6381Phosphothreonine; by autocatalysis By similarity
Modified residue6511Phosphoserine By similarity
Modified residue6571Phosphoserine By similarity
Modified residue6581Phosphotyrosine; by SYK Ref.7

Natural variations

Natural variant1061I → V in mutant form UV25. Ref.2
Natural variant1111S → G in mutant form UV25. Ref.2
Natural variant2401L → Q in mutant form UV25. Ref.2
Natural variant3391F → L in mutant form UV25. Ref.2

Experimental info

Sequence conflict1471D → V in CAA36908. Ref.1
Sequence conflict1471D → V in CAA36907. Ref.1
Sequence conflict2181N → T in CAA36908. Ref.1
Sequence conflict2181N → T in CAA36907. Ref.1
Sequence conflict277 – 2782AH → LL in CAA36908. Ref.1
Sequence conflict277 – 2782AH → LL in CAA36907. Ref.1
Sequence conflict3131V → A in CAA36908. Ref.1
Sequence conflict3131V → A in CAA36907. Ref.1
Sequence conflict4671N → D in CAA36908. Ref.1
Sequence conflict4671N → D in CAA36907. Ref.1
Sequence conflict4721N → D in CAA36908. Ref.1
Sequence conflict4721N → D in CAA36907. Ref.1
Sequence conflict5761Q → H in CAA36908. Ref.1
Sequence conflict5761Q → H in CAA36907. Ref.1

Sequences

Sequence LengthMass (Da)Tools
P20444 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 394B48C952BB6D50

FASTA67276,852
        10         20         30         40         50         60 
MADVYPANDS TASQDVANRF ARKGALRQKN VHEVKDHKFI ARFFKQPTFC SHCTDFIWGF 

        70         80         90        100        110        120 
GKQGFQCQVC CFVVHKRCHE FVTFSCPGAD KGPDTDDPRS KHKFKIHTYG SPTFCDHCGS 

       130        140        150        160        170        180 
LLYGLIHQGM KCDTCDMNVH KQCVINDPSL CGMDHTEKRG RIYLKAEVTD EKLHVTVRDA 

       190        200        210        220        230        240 
KNLIPMDPNG LSDPYVKLKL IPDPKNESKQ KTKTIRSNLN PQWNESFTFK LKPSDKDRRL 

       250        260        270        280        290        300 
SVEIWDWDRT TRNDFMGSLS FGVSELMKMP ASGWYKAHNQ EEGEYYNVPI PEGDEEGNME 

       310        320        330        340        350        360 
LRQKFEKAKL GPVGNKVISP SEDRKQPSNN LDRVKLTDFN FLMVLGKGSF GKVMLADRKG 

       370        380        390        400        410        420 
TEELYAIKIL KKDVVIQDDD VECTMVEKRV LALLDKPPFL TQLHSCFQTV DRLYFVMEYV 

       430        440        450        460        470        480 
NGGDLMYHIQ QVGKFKEPQA VFYAAEISIG LFFLHKRGII YRDLKLNNVM LNSEGHIKIA 

       490        500        510        520        530        540 
DFGMCKEHMM DGVTTRTFCG TPDYIAPEII AYQPYGKSVD WWAYGVLLYE MLAGQPPFDG 

       550        560        570        580        590        600 
EDEDELFQSI MEHNVSYPKS LSKEAVSICK GLMTKQPAKR LGCGPEGERD VREHAFFRRI 

       610        620        630        640        650        660 
DWEKLENREI QPPFKPKVCG KGAENFDKFF TRGQPVLTPP DQLVIANIDQ SDFEGFSYVN 

       670 
PQFVHPILQS AV 

« Hide

References

[1]"Molecular cloning of mouse protein kinase C (PKC) cDNA from Swiss 3T3 fibroblasts."
Rose-John S., Dietrich A., Marks F.
Gene 74:465-471(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"A mutant protein kinase C that can transform fibroblasts."
Megidish T., Mazurek N.
Nature 342:807-811(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS VAL-106; GLY-111; GLN-240 AND LEU-339.
Strain: BALB/c.
Tissue: Brain.
[3]"Protein kinase C alpha activates RAF-1 by direct phosphorylation."
Kolch W., Heidecker G., Kochs G., Hummel R., Vahidi H., Mischak H., Finkenzeller G., Marme D., Rapp U.R.
Nature 364:249-252(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF RAF1.
[4]"PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system."
Staudinger J., Zhou J., Burgess R., Elledge S.J., Olson E.N.
J. Cell Biol. 128:263-271(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PRKCABP.
[5]"An activated protein kinase C alpha gives a differentiation signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating factor-stimulated signaling events."
Pierce A., Heyworth C.M., Nicholls S.E., Spooncer E., Dexter T.M., Lord J.M., Owen-Lynch P.J., Wark G., Whetton A.D.
J. Cell Biol. 140:1511-1518(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL PROLIFERATION.
[6]"Imaging protein kinase Calpha activation in cells."
Ng T., Squire A., Hansra G., Bornancin F., Prevostel C., Hanby A., Harris W., Barnes D., Schmidt S., Mellor H., Bastiaens P.I., Parker P.J.
Science 283:2085-2089(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[7]"A Ras activation pathway dependent on Syk phosphorylation of protein kinase C."
Kawakami Y., Kitaura J., Yao L., McHenry R.W., Kawakami Y., Newton A.C., Kang S., Kato R.M., Leitges M., Rawlings D.J., Kawakami T.
Proc. Natl. Acad. Sci. U.S.A. 100:9470-9475(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-658.
[8]"PKCalpha regulates platelet granule secretion and thrombus formation in mice."
Konopatskaya O., Gilio K., Harper M.T., Zhao Y., Cosemans J.M., Karim Z.A., Whiteheart S.W., Molkentin J.D., Verkade P., Watson S.P., Heemskerk J.W., Poole A.W.
J. Clin. Invest. 119:399-407(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PLATELET GRANULE SECRETION.
[9]"Identification of RACK1 and protein kinase Calpha as integral components of the mammalian circadian clock."
Robles M.S., Boyault C., Knutti D., Padmanabhan K., Weitz C.J.
Science 327:463-466(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BMAL1 AND GNB2L1, SUBCELLULAR LOCATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M25811 mRNA. Translation: AAA39934.1.
X52685 mRNA. Translation: CAA36908.1.
X52684 mRNA. Translation: CAA36907.1.
PIRKIMSCA. S07104.
RefSeqNP_035231.2. NM_011101.3.
UniGeneMm.222178.

3D structure databases

ProteinModelPortalP20444.
SMRP20444. Positions 37-670.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid202194. 8 interactions.
DIPDIP-532N.
IntActP20444. 3 interactions.
MINTMINT-98140.

Chemistry

BindingDBP20444.
ChEMBLCHEMBL2567.

PTM databases

PhosphoSiteP20444.

Proteomic databases

PaxDbP20444.
PRIDEP20444.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID18750.
KEGGmmu:18750.

Organism-specific databases

CTD5578.
MGIMGI:97595. Prkca.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233022.
HOVERGENHBG108317.
InParanoidP20444.
KOK02677.
PhylomeDBP20444.

Enzyme and pathway databases

BRENDA2.7.11.13. 3474.

Gene expression databases

CleanExMM_PRKCA.
GenevestigatorP20444.

Family and domain databases

Gene3D2.60.40.150. 1 hit.
InterProIPR000961. AGC-kinase_C.
IPR000008. C2_dom.
IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR017892. Pkinase_C.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR014375. Protein_kinase_C_a/b/g.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00130. C1_1. 2 hits.
PF00168. C2. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]
PIRSFPIRSF000550. PKC_alpha. 1 hit.
PRINTSPR00360. C2DOMAIN.
PR00008. DAGPEDOMAIN.
SMARTSM00109. C1. 2 hits.
SM00239. C2. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS51285. 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.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPRKCA. mouse.
NextBio294917.
PROP20444.
SOURCESearch...

Entry information

Entry nameKPCA_MOUSE
AccessionPrimary (citable) accession number: P20444
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1991
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 152 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot