P05696 (KPCA_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	672 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 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. Ref.4 Ref.5 Ref.6
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 By similarity. Ref.3
Subcellular location	Cytoplasm. Cell membrane; Peripheral membrane protein. Mitochondrion membrane; Peripheral membrane protein By similarity. Nucleus. Note: Translocated to the nucleus upon treatment with PMA or IGF1. Ref.6 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.

Ontologies

Keywords
Biological process	Angiogenesis Apoptosis Cell adhesion
Cellular component	Cell membrane Cytoplasm Membrane Mitochondrion Nucleus
Domain	Repeat Zinc-finger
Ligand	ATP-binding Calcium Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	aging Inferred from expression pattern. Source: RGD central nervous system neuron axonogenesis Inferred from mutant phenotype. Source: RGD establishment of protein localization Traceable author statement. Source: UniProtKB intracellular signal transduction Inferred from direct assay. Source: RGD learning or memory Inferred from mutant phenotype. Source: RGD negative regulation of heart contraction Inferred from mutant phenotype. Source: RGD negative regulation of translation Inferred from mutant phenotype. Source: RGD peptidyl-serine phosphorylation Inferred from direct assay. Source: RGD positive regulation of exocytosis Inferred from mutant phenotype. Source: RGD positive regulation of smooth muscle cell proliferation Inferred from mutant phenotype. Source: RGD positive regulation of synapse assembly Inferred from mutant phenotype. Source: RGD protein autophosphorylation Inferred from direct assay. Source: RGD regulation of receptor-mediated endocytosis Inferred from mutant phenotype. Source: RGD response to antibiotic Inferred from expression pattern. Source: RGD response to corticosterone stimulus Inferred from expression pattern. Source: RGD response to estradiol stimulus Inferred from mutant phenotype. Source: RGD response to ethanol Inferred from mutant phenotype. Source: RGD response to mechanical stimulus Inferred from expression pattern. Source: RGD response to organic cyclic compound Inferred from expression pattern. Source: RGD response to peptide hormone stimulus Inferred from expression pattern. Source: RGD response to reactive oxygen species Inferred from mutant phenotype. Source: RGD response to toxin Inferred from expression pattern. Source: RGD
Cellular component	cytosol Inferred from direct assay. Source: RGD membrane raft Inferred from direct assay. Source: RGD mitochondrion Inferred from direct assay. Source: RGD nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from direct assay. Source: RGD protein complex Inferred from direct assay. Source: RGD synaptosome Inferred from direct assay. Source: RGD
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW calcium-dependent protein kinase C activity Inferred from direct assay. Source: RGD zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed By similarity

Chain

2 – 672

671

Protein kinase C alpha type

PRO_0000055682

Regions

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

Sites

Active site

463

1

Proton acceptor By similarity

Metal binding

186

1

Calcium 1; via carbonyl oxygen

Metal binding

187

1

Calcium 1

Metal binding

187

1

Calcium 2

Metal binding

193

1

Calcium 2

Metal binding

246

1

Calcium 1

Metal binding

246

1

Calcium 2

Metal binding

247

1

Calcium 2; via carbonyl oxygen

Metal binding

248

1

Calcium 1

Metal binding

248

1

Calcium 2

Metal binding

248

1

Calcium 3

Metal binding

252

1

Calcium 3; via carbonyl oxygen

Metal binding

254

1

Calcium 1

Metal binding

254

1

Calcium 3

Binding site

195

1

Inositol phosphate group

Binding site

245

1

Inositol phosphate group

Binding site

368

1

ATP By similarity

Amino acid modifications

Modified residue

2

1

N-acetylalanine By similarity

Modified residue

195

1

Phosphotyrosine By similarity

Modified residue

208

1

Phosphoserine By similarity

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 By similarity

Modified residue

495

1

Phosphothreonine By similarity

Modified residue

497

1

Phosphothreonine; by PDPK1 By similarity

Modified residue

501

1

Phosphothreonine By similarity

Modified residue

604

1

N6-acetyllysine By similarity

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

657

1

Phosphoserine By similarity

Modified residue

658

1

Phosphotyrosine; by SYK By similarity

Experimental info

Mutagenesis

195

1

Y → S: Reduced phosphatidylinositol 4,5-bisphosphate recognition and impaired membrane docking. Loss of phosphatidylinositol 4,5-bisphosphate-binding and strong decrease of membrane docking; when associated with A-209; A-211 and A-245. Ref.9

Mutagenesis

209

1

K → A: Loss of phosphatidylinositol 4,5-bisphosphate-binding and strong decrease of membrane docking; when associated with S-195; A-211 and A-245. Ref.9

Mutagenesis

211

1

K → A: Loss of phosphatidylinositol 4,5-bisphosphate-binding and strong decrease of membrane docking; when associated with S-195; A-209 and A-245. Ref.9

Mutagenesis

245

1

W → A: Reduced phosphatidylinositol 4,5-bisphosphate recognition and impaired membrane docking. Loss of phosphatidylinositol 4,5-bisphosphate-binding and strong decrease of membrane docking; when associated with S-195; A-209 and A-211. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

672

Helix Strand Turn

Details...

Beta strand

161 – 168

8

Beta strand

170 – 182

13

Beta strand

194 – 202

9

Beta strand

222 – 230

9

Helix

233 – 235

3

Beta strand

239 – 246

8

Beta strand

249 – 251

3

Beta strand

254 – 262

9

Helix

263 – 268

6

Beta strand

271 – 276

6

Helix

280 – 283

4

Beta strand

288 – 290

3

Sequences

	Sequence		Length	Mass (Da)
	P05696 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 94889E7339C17719	FASTA	672	76,792
	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 KQCVINVPSL CGMDHTEKRG RIYLKAEVTD EKLHVTVRDA 190 200 210 220 230 240 KNLIPMDPNG LSDPYVKLKL IPDPKNESKQ KTKTIRSTLN PQWNESFTFK LKPSDKDRRL 250 260 270 280 290 300 SVEIWDWDRT TRNDFMGSLS FGVSELMKMP ASGWYKLLNQ EEGEYYNVPI PEGDEEGNVE 310 320 330 340 350 360 LRQKFEKAKL GPAGNKVISP 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 YRDLKLDNVM LDSEGHIKIA 490 500 510 520 530 540 DFGMCKEHMM DGVTTRTFCG TPDYIAPEII AYQPYGKSVD WWAYGVLLYE MLAGQPPFDG 550 560 570 580 590 600 EDEDELFQSI MEHNVSYPKS LSKEAVSICK GLMTKHPAKR LGCGPEGERD VREHAFFRRI 610 620 630 640 650 660 DWEKLENREI QPPFKPKVCG KGAENFDKFF TRGQPVLTPP DQLVIANIDQ SDFEGFSYVN 670 PQFVHPILQS AV

References

[1]	"Nucleotide sequences of cDNAs for alpha and gamma subspecies of rat brain protein kinase C." Ono Y., Fujii T., Igarashi K., Kikkawa U., Ogita K., Nishizuka Y. Nucleic Acids Res. 16:5199-5200(1988) [PubMed: 3387228] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"The common structure and activities of four subspecies of rat brain protein kinase C family." Kikkawa U., Ogita K., Ono Y., Asaoka Y., Shearman M.S., Fujii T., Ase K., Sekiguchi K., Igarashi K., Nishizuka Y. FEBS Lett. 223:212-216(1987) [PubMed: 3666147] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"Targeting of protein kinase Calpha to caveolae." Mineo C., Ying Y.-S., Chapline C., Jaken S., Anderson R.G.W. J. Cell Biol. 141:601-610(1998) [PubMed: 9566962] [Abstract] Cited for: INTERACTION WITH SDPR.
[4]	"Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium." Frey M.R., Clark J.A., Leontieva O., Uronis J.M., Black A.R., Black J.D. J. Cell Biol. 151:763-778(2000) [PubMed: 11076962] [Abstract] Cited for: FUNCTION IN CELL CYCLE ARREST.
[5]	"PKC alpha regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase1/2 (ERK1/2)." Braz J.C., Bueno O.F., De Windt L.J., Molkentin J.D. J. Cell Biol. 156:905-919(2002) [PubMed: 11864993] [Abstract] Cited for: FUNCTION IN CARDIAC HYPETROPHY.
[6]	"Protein kinase C-alpha-induced hypertrophy of neonatal rat ventricular myocytes." Vijayan K., Szotek E.L., Martin J.L., Samarel A.M. Am. J. Physiol. 287:H2777-H2789(2004) [PubMed: 15271671] [Abstract] Cited for: FUNCTION IN HEART FAILURE, SUBCELLULAR LOCATION.
[7]	"The molecular heterogeneity of protein kinase C and its implications for cellular regulation." Nishizuka Y. Nature 334:661-665(1988) [PubMed: 3045562] [Abstract] Cited for: REVIEW.
[8]	"Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine." Verdaguer N., Corbalan-Garcia S., Ochoa W.F., Fita I., Gomez-Fernandez J.C. EMBO J. 18:6329-6338(1999) [PubMed: 10562545] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 155-293 IN COMPLEX WITH PHOSPHATIDYLSERINE.
[9]	"Structural and mechanistic insights into the association of PKCalpha-C2 domain to PtdIns(4,5)P2." Guerrero-Valero M., Ferrer-Orta C., Querol-Audi J., Marin-Vicente C., Fita I., Gomez-Fernandez J.C., Verdaguer N., Corbalan-Garcia S. Proc. Natl. Acad. Sci. U.S.A. 106:6603-6607(2009) [PubMed: 19346474] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 156-292 IN COMPLEX WITH PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE, MUTAGENESIS OF TYR-195; LYS-209; LYS-211 AND TRP-245, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X07286 mRNA. Translation: CAA30266.1.

IPI

IPI00201792.

PIR

KIRTC. S02248.

UniGene

Rn.207908.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DSY	X-ray	2.60	A	155-293	[»]
3GPE	X-ray	2.00	A	156-292	[»]
3RDJ	X-ray	1.90	A	156-292	[»]
3TWY	X-ray	1.50	A	156-292	[»]

ProteinModelPortal

P05696.

SMR

P05696. Positions 37-292, 336-666.

ModBase

Search...

Protein-protein interaction databases

IntAct

P05696. 2 interactions.

MINT

MINT-86103.

STRING

P05696.

PTM databases

PhosphoSite

P05696.

Proteomic databases

PRIDE

P05696.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Organism-specific databases

RGD

3395. Prkca.

Phylogenomic databases

eggNOG

maNOG08253.

GeneTree

ENSGT00590000082854.

HOVERGEN

HBG108317.

OrthoDB

EOG40ZQX0.

PhylomeDB

P05696.

Enzyme and pathway databases

BRENDA

2.7.11.13. 5301.

Gene expression databases

ArrayExpress

P05696.

Genevestigator

P05696.

GermOnline

ENSRNOG00000003491. Rattus norvegicus.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR000008. C2_Ca-dep.
IPR008973. C2_Ca/lipid-bd_dom_CaLB.
IPR020477. C2_dom.
IPR018029. C2_membr_targeting.
IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR017892. Pkinase_C.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR014375. Protein_kinase_C_a/b/g.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]

Pfam

PF00130. C1_1. 2 hits.
PF00168. C2. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]

PIRSF

PIRSF000550. PKC_alpha. 1 hit.

PRINTS

PR00360. C2DOMAIN.
PR00008. DAGPEDOMAIN.

SMART

SM00109. C1. 2 hits.
SM00239. C2. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

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.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

KPCA_RAT

Accession

Primary (citable) accession number: P05696

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1988
Last sequence update:	January 23, 2007
Last modified:	January 25, 2012
This is version 136 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program