P09216 (KPCE_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein kinase C epsilon type
EC=2.7.11.13

Alternative name(s):
nPKC-epsilon

Gene names

Name:	Prkce
Synonyms:	Pkce

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	737 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F-actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL-mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1. Ref.4 Ref.6 Ref.7
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-566 (activation loop of the kinase domain), Thr-710 (turn motif) and Ser-729 (hydrophobic region), need to be phosphorylated for its full activation.
Subunit structure	Interacts with DGKQ, STAT3 and YWHAB By similarity. Forms a ternary complex with TRIM63 and GN2BL1. Can form a complex with PDLIM5 and N-type calcium channel. Interacts with COPB1. Ref.3 Ref.5 Ref.6
Subcellular location	Cytoplasm By similarity. Cytoplasm › cytoskeleton By similarity. Cell membrane By similarity. Cytoplasm › perinuclear region By similarity. Nucleus By similarity. Note: Translocated to plasma membrane in epithelial cells stimulated by HGF. Associated with the Golgi at the perinuclear site in pre-passage fibroblasts. In passaging cells, translocated to the cell periphery. Translocated to the nucleus in PMA-treated cells By similarity. Ref.3
Domain	The C1 domain, containing the phorbol ester/DAG-type region 1 (C1A) and 2 (C1B), is the diacylglycerol sensor and the C2 domain is a non-calcium binding domain.
Post-translational modification	Phosphorylation on Thr-566 by PDPK1 triggers autophosphorylation on Ser-729. Phosphorylation in the hinge domain at Ser-350 by MAPK11 or MAPK14, Ser-346 by GSK3B and Ser-368 by autophosphorylation is required for interaction with YWHAB By similarity.
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	Cell adhesion Cell cycle Cell division Immunity
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Nucleus
Domain	Repeat Zinc-finger
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	TRAM-dependent toll-like receptor 4 signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell division Inferred from electronic annotation. Source: UniProtKB-KW intracellular signal transduction Inferred from direct assay PubMed 11562372. Source: RGD lipopolysaccharide-mediated signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from mutant phenotype PubMed 20383739. Source: UniProtKB negative regulation of mitochondrial membrane potential Inferred from mutant phenotype PubMed 20383739. Source: UniProtKB negative regulation of release of sequestered calcium ion into cytosol Inferred from mutant phenotype PubMed 20383739. Source: UniProtKB positive regulation of actin filament polymerization Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell cycle cytokinesis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of epithelial cell migration Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of fibroblast migration Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of wound healing Inferred from sequence or structural similarity. Source: UniProtKB reduction of mitochondrial calcium ion concentration Inferred from mutant phenotype PubMed 20383739. Source: UniProtKB
Cellular_component	Golgi membrane Inferred from direct assay Ref.3. Source: RGD cytoskeleton Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Inferred from direct assay PubMed 18945317PubMed 9705215PubMed 9950866. Source: RGD nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell perinuclear region of cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from direct assay PubMed 18945317. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW actin monomer binding Inferred from sequence or structural similarity. Source: UniProtKB calcium-independent protein kinase C activity Inferred from electronic annotation. Source: InterPro metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 737

737

Protein kinase C epsilon type

PRO_0000055700

Regions

Domain

1 – 99

99

C2

Domain

408 – 668

261

Protein kinase

Domain

669 – 737

69

AGC-kinase C-terminal

Zinc finger

169 – 220

52

Phorbol-ester/DAG-type 1

Zinc finger

242 – 292

51

Phorbol-ester/DAG-type 2

Nucleotide binding

414 – 422

9

ATP By similarity

Motif

223 – 228

6

Interaction with actin By similarity

Sites

Active site

532

1

Proton acceptor By similarity

Binding site

437

1

ATP By similarity

Amino acid modifications

Modified residue

228

1

Phosphothreonine By similarity

Modified residue

234

1

Phosphoserine By similarity

Modified residue

309

1

Phosphothreonine By similarity

Modified residue

316

1

Phosphoserine By similarity

Modified residue

329

1

Phosphoserine By similarity

Modified residue

337

1

Phosphoserine By similarity

Modified residue

346

1

Phosphoserine; by GSK3-beta By similarity

Modified residue

349

1

Phosphothreonine By similarity

Modified residue

350

1

Phosphoserine; by MAPK11 and MAPK14 By similarity

Modified residue

368

1

Phosphoserine; by autocatalysis By similarity

Modified residue

388

1

Phosphoserine By similarity

Modified residue

566

1

Phosphothreonine; by PDPK1 By similarity

Modified residue

703

1

Phosphothreonine; by autocatalysis Potential

Modified residue

710

1

Phosphothreonine; by autocatalysis Potential

Modified residue

729

1

Phosphoserine; by autocatalysis By similarity

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

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737

Helix Strand Turn

Details...

Beta strand

4 – 17

14

Helix

22 – 25

4

Beta strand

40 – 46

7

Beta strand

49 – 53

5

Beta strand

64 – 76

13

Beta strand

78 – 85

8

Beta strand

88 – 91

4

Beta strand

93 – 101

9

Helix

102 – 105

4

Beta strand

111 – 118

8

Beta strand

120 – 122

3

Beta strand

124 – 135

12

Sequences

	Sequence		Length	Mass (Da)
	P09216 [UniParc]. Last modified July 1, 1989. Version 1. Checksum: 6AD6999EFDD2659F	FASTA	737	83,478
	10 20 30 40 50 60 MVVFNGLLKI KICEAVSLKP TAWSLRHAVG PRPQTFLLDP YIALNVDDSR IGQTATKQKT 70 80 90 100 110 120 NSPAWHDEFV TDVCNGRKIE LAVFHDAPIG YDDFVANCTI QFEELLQNGS RHFEDWIDLE 130 140 150 160 170 180 PEGKVYVIID LSGSSGEAPK DNEERVFRER MRPRKRQGAV RRRVHQVNGH KFMATYLRQP 190 200 210 220 230 240 TYCSHCRDFI WGVIGKQGYQ CQVCTCVVHK RCHELIITKC AGLKKQETPD EVGSQRFSVN 250 260 270 280 290 300 MPHKFGIHNY KVPTFCDHCG SLLWGLLRQG LQCKVCKMNV HRRCETNVAP NCGVDARGIA 310 320 330 340 350 360 KVLADLGVTP DKITNSGQRR KKLAAGAESP QPASGNSPSE DDRSKSAPTS PCDQELKELE 370 380 390 400 410 420 NNIRKALSFD NRGEEHRASS STDGQLASPG ENGEVRQGQA KRLGLDEFNF IKVLGKGSFG 430 440 450 460 470 480 KVMLAELKGK DEVYAVKVLK KDVILQDDDV DCTMTEKRIL ALARKHPYLT QLYCCFQTKD 490 500 510 520 530 540 RLFFVMEYVN GGDLMFQIQR SRKFDEPRSG FYAAEVTSAL MFLHQHGVIY RDLKLDNILL 550 560 570 580 590 600 DAEGHSKLAD FGMCKEGILN GVTTTTFCGT PDYIAPEILQ ELEYGPSVDW WALGVLMYEM 610 620 630 640 650 660 MAGQPPFEAD NEDDLFESIL HDDVLYPVWL SKEAVSILKA FMTKNPHKRL GCVAAQNGED 670 680 690 700 710 720 AIKQHPFFKE IDWVLLEQKK MKPPFKPRIK TKRDVNNFDQ DFTREEPILT LVDEAIVKQI 730 NQEEFKGFSY FGEDLMP

References

[1]	"The structure, expression, and properties of additional members of the protein kinase C family." Ono Y., Fujii T., Ogita K., Kikkawa U., Igarashi K., Nishizuka Y. J. Biol. Chem. 263:6927-6932(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"Identification of three additional members of rat protein kinase C family: delta-, epsilon- and zeta-subspecies." Ono Y., Fujii T., Ogita K., Kikkawa U., Igarashi K., Nishizuka Y. FEBS Lett. 226:125-128(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 135-297.
[3]	"The coatomer protein beta'-COP, a selective binding protein (RACK) for protein kinase Cepsilon." Csukai M., Chen C.-H., de Matteis M.A., Mochly-Rosen D. J. Biol. Chem. 272:29200-29206(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH COPB1, SUBCELLULAR LOCATION.
[4]	"Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C." Matsumoto M., Ogawa W., Hino Y., Furukawa K., Ono Y., Takahashi M., Ohba M., Kuroki T., Kasuga M. J. Biol. Chem. 276:14400-14406(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF AKT1.
[5]	"Muscle ring finger protein-1 inhibits PKC-epsilon activation and prevents cardiomyocyte hypertrophy." Arya R., Kedar V., Hwang J.R., McDonough H., Li H.-H., Taylor J., Patterson C. J. Cell Biol. 167:1147-1159(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GNB2L1 AND TRIM63.
[6]	"A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels." Maeno-Hikichi Y., Chang S., Matsumura K., Lai M., Lin H., Nakagawa N., Kuroda S., Zhang J.F. Nat. Neurosci. 6:468-475(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN A COMPLEX WITH PDLIM5 AND N-TYPE CALCIUM CHANNEL.
[7]	"Protein kinase Cepsilon-dependent MARCKS phosphorylation in neonatal and adult rat ventricular myocytes." Heidkamp M.C., Iyengar R., Szotek E.L., Cribbs L.L., Samarel A.M. J. Mol. Cell. Cardiol. 42:422-431(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF MARCKS.
[8]	"Structure of the C2 domain from novel protein kinase Cepsilon. A membrane binding model for Ca(2+)-independent C2 domains." Ochoa W.F., Garcia-Garcia J., Fita I., Corbalan-Garcia S., Verdaguer N., Gomez-Fernandez J.C. J. Mol. Biol. 311:837-849(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-136.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M18331 mRNA. Translation: AAA41872.1.

IPI

IPI00551781.

PIR

KIRTCE. B28163.

RefSeq

NP_058867.1. NM_017171.1.

UniGene

Rn.215207.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GMI	X-ray	1.70	A	1-136	[»]

ProteinModelPortal

P09216.

SMR

P09216. Positions 1-136, 239-295, 405-736.

ModBase

Search...

Protein-protein interaction databases

IntAct

P09216. 3 interactions.

STRING

10116.ENSRNOP00000020959.

PTM databases

PhosphoSite

P09216.

Proteomic databases

PaxDb

P09216.

PRIDE

P09216.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

29340.

KEGG

rno:29340.

UCSC

RGD:61925. rat.

Organism-specific databases

CTD

5581.

RGD

61925. Prkce.

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233022.

HOVERGEN

HBG108317.

KO

K06068.

OrthoDB

EOG40P467.

Enzyme and pathway databases

BRENDA

2.7.11.13. 5301.

Gene expression databases

ArrayExpress

P09216.

Genevestigator

P09216.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR000008. C2_Ca-dep.
IPR008973. C2_Ca/lipid-bd_dom_CaLB.
IPR018029. C2_membr_targeting.
IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR027274. PKC_epsilon.
IPR017892. Pkinase_C.
IPR014376. Prot_kin_PKC_delta.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

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

PIRSF

PIRSF000551. PKC_delta. 1 hit.
PIRSF501106. Protein_kin_C_epsilon. 1 hit.

PRINTS

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...

Other

BindingDB

P09216.

ChEMBL

CHEMBL3424.

EvolutionaryTrace

P09216.

NextBio

608832.

Entry information

Entry name

KPCE_RAT

Accession

Primary (citable) accession number: P09216

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	July 1, 1989
Last modified:	May 1, 2013
This is version 131 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program