Q62074 (KPCI_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein kinase C iota type
EC=2.7.11.13

Alternative name(s):
Atypical protein kinase C-lambda/iota
Short name=aPKC-lambda/iota
nPKC-iota

Gene names

Name:	Prkci
Synonyms:	Pkcl

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [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 › Mus › Mus

Protein attributes

Sequence length	595 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- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI3K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis By similarity. Downstream of PI3K is required for insulin-stimulated glucose transport. Activates RAB4A and promotes its association with KIF3A which is required for the insulin-induced SLC2A4/GLUT4 translocation in adipocytes. Is essential in early embryogenesis and development of differentiating photoreceptors by playing a role in the establishment of epithelial and neuronal polarity. Ref.3 Ref.6 Ref.7 Ref.8 Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-411 (activation loop of the kinase domain) and Thr-563 (turn motif), need to be phosphorylated for its full activation By similarity. Might also be a target for novel lipid activators that are elevated during nutrient-stimulated insulin secretion.
Subunit structure	Forms a complex with SQSTM1 and MP2K5 By similarity. Interacts directly with SQSTM1 Probable. Interacts with IKBKB. Interacts with PARD6A, PARD6B and PARD6G. Part of a quaternary complex containing aPKC, PARD3, a PARD6 protein (PARD6A, PARD6B or PARD6G) and a GTPase protein (CDC42 or RAC1). Part of a complex with LLGL1 and PARD6B. Interacts with ADAP1/CENTA1. Interaction with SMG1, through the ZN-finger domain, activates the kinase activity. Interacts with CDK7. Forms a complex with RAB2A and GAPDH involved in recruitment onto the membrane of vesicular tubular clusters (VTCs). Interacts with ECT2 ('Thr-359' phosphorylated form) By similarity. Ref.4 Ref.5
Subcellular location	Cytoplasm By similarity. Membrane By similarity. Endosome By similarity. Nucleus By similarity. Note: Transported into the endosome through interaction with SQSTM1/p62. After phosphorylation by SRC, transported into the nucleus through interaction with KPNB1. Colocalizes with CDK7 in the cytoplasm and nucleus. Transported to vesicular tubular clusters (VTCs) through interaction with RAB2A By similarity.
Domain	The OPR domain mediates interaction with SQSTM1. The C1 zinc finger does not bind diacylglycerol (DAG) By similarity. The pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins, except the presence of a non-phosphorylatable residue in place of Ser, it modulates activity by competing with substrates.
Post-translational modification	Upon neuronal growth factor (NGF) stimulation, phosphorylated by SRC at Tyr-264, Tyr-279 and Tyr-333. Phosphorylation on Tyr-264 facilitates binding to KPNB1/importin-beta regulating entry of PRKCI into the nucleus. Phosphorylation on Tyr-333 is important for NF-kappa-B stimulation By similarity. Phosphorylation at Thr-411 in the activation loop is not mandatory for activation. Ref.10
Disruption phenotype	Embryonic lethal at 9.5 dpc. Ref.7
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 OPR domain. Contains 1 phorbol-ester/DAG-type zinc finger. Contains 1 protein kinase domain.
Sequence caution	The sequence AAH21630.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAA32499.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Cellular component	Cytoplasm Endosome Membrane Nucleus
Disease	Proto-oncogene Tumor suppressor
Domain	Zinc-finger
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Golgi vesicle budding Inferred from electronic annotation. Source: Compara actin filament organization Inferred from mutant phenotype Ref.7. Source: MGI cell migration Inferred from electronic annotation. Source: Compara cell-cell junction organization Inferred from sequence or structural similarity. Source: UniProtKB cellular protein localization Inferred from electronic annotation. Source: Compara cellular response to insulin stimulus Inferred from mutant phenotype PubMed 9819385. Source: BHF-UCL establishment of apical/basal cell polarity Inferred from mutant phenotype Ref.9. Source: MGI eye photoreceptor cell development Inferred from mutant phenotype Ref.9. Source: MGI intracellular signal transduction Inferred from electronic annotation. Source: InterPro negative regulation of glial cell apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of neuron apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of endothelial cell apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of establishment of protein localization to plasma membrane Inferred from mutant phenotype PubMed 9819385. Source: BHF-UCL positive regulation of glial cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of glucose import Inferred from mutant phenotype PubMed 9819385. Source: BHF-UCL positive regulation of neuron projection development Inferred from sequence or structural similarity. Source: UniProtKB response to interleukin-1 Inferred from electronic annotation. Source: Compara
Cellular_component	Schmidt-Lanterman incisure Inferred from direct assay PubMed 20237282. Source: BHF-UCL apical plasma membrane Inferred from direct assay PubMed 16892058. Source: MGI cell leading edge Inferred from electronic annotation. Source: Compara cytosol Inferred from sequence or structural similarity. Source: UniProtKB endosome Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from sequence or structural similarity. Source: UniProtKB protein complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid binding Inferred from sequence or structural similarity. Source: UniProtKB protein kinase C activity Inferred from direct assay PubMed 9819385. Source: BHF-UCL 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 – 595

594

Protein kinase C iota type

PRO_0000055711

Regions

Domain

25 – 108

84

OPR

Domain

253 – 521

269

Protein kinase

Domain

522 – 595

74

AGC-kinase C-terminal

Zinc finger

140 – 190

51

Phorbol-ester/DAG-type

Nucleotide binding

259 – 267

9

ATP By similarity

Region

2 – 252

251

Regulatory domain By similarity

Region

2 – 28

27

Required for interaction with RAB2 By similarity

Region

72 – 91

20

Interaction with PARD6A By similarity

Motif

125 – 134

10

Pseudosubstrate

Sites

Active site

377

1

Proton acceptor By similarity

Binding site

282

1

ATP By similarity

Amino acid modifications

Modified residue

2

1

N-acetylproline By similarity

Modified residue

3

1

Phosphothreonine By similarity

Modified residue

7

1

Phosphoserine By similarity

Modified residue

8

1

Phosphoserine By similarity

Modified residue

9

1

Phosphothreonine By similarity

Modified residue

264

1

Phosphotyrosine; by SRC By similarity

Modified residue

279

1

Phosphotyrosine; by SRC By similarity

Modified residue

333

1

Phosphotyrosine; by SRC By similarity

Modified residue

411

1

Phosphothreonine; by PDPK1 By similarity

Modified residue

563

1

Phosphothreonine Ref.10

Experimental info

Mutagenesis

27

1

R → A: No effect on interaction with SQSTM1. Ref.5

Mutagenesis

28

1

V → A: No effect on interaction with SQSTM1; when associated with A-29. Ref.5

Mutagenesis

29

1

K → A: No effect on interaction with SQSTM1; when associated with A-118. Ref.5

Mutagenesis

70

1

W → A: Loss of interaction with SQSTM1. Ref.5

Mutagenesis

72

1

D → A: Loss of interaction with SQSTM1. Ref.5

Mutagenesis

74

1

E → A: Loss of interaction with SQSTM1. Ref.5

Mutagenesis

76

1

D → A: Loss of interaction with SQSTM1. Ref.5

Mutagenesis

83

1

Q → A: No effect on interaction with SQSTM1. Ref.5

Mutagenesis

85

1

E → A: Loss of interaction with SQSTM1. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

595

Helix Strand Turn

Details...

Helix

250 – 252

3

Beta strand

253 – 261

9

Beta strand

263 – 272

10

Turn

273 – 275

3

Beta strand

278 – 285

8

Helix

286 – 288

3

Helix

297 – 308

12

Beta strand

317 – 322

6

Beta strand

324 – 332

9

Helix

339 – 346

8

Helix

351 – 370

20

Helix

380 – 382

3

Beta strand

383 – 385

3

Beta strand

391 – 393

3

Helix

416 – 418

3

Helix

421 – 424

4

Helix

432 – 447

16

Turn

453 – 456

4

Helix

466 – 475

10

Helix

486 – 495

10

Turn

500 – 502

3

Turn

508 – 510

3

Helix

511 – 517

7

Turn

519 – 523

5

Helix

526 – 530

5

Helix

548 – 550

3

Helix

553 – 556

4

Helix

567 – 570

4

Helix

575 – 578

4

Sequences

	Sequence		Length	Mass (Da)
	Q62074 [UniParc]. Last modified June 16, 2009. Version 3. Checksum: 6AC612D1E9264825	FASTA	595	68,203
	10 20 30 40 50 60 MPTQRDSSTM SHTVACGGGG DHSHQVRVKA YYRGDIMITH FEPSISFEGL CSEVRDMCSF 70 80 90 100 110 120 DNEQPFTMKW IDEEGDPCTV SSQLELEEAF RLYELNKDSE LLIHVFPCVP ERPGMPCPGE 130 140 150 160 170 180 DKSIYRRGAR RWRKLYCANG HTFQAKRFNR RAHCAICTDR IWGLGRQGYK CINCKLLVHK 190 200 210 220 230 240 KCHKLVTIEC GRHSLPPEPM MPMDQTMHPD HTQTVIPYNP SSHESLDQVG EEKEAMNTRE 250 260 270 280 290 300 SGKASSSLGL QDFDLLRVIG RGSYAKVLLV RLKKTDRIYA MKVVKKELVN DDEDIDWVQT 310 320 330 340 350 360 EKHVFEQASN HPFLVGLHSC FQTESRLFFV IEYVNGGDLM FHMQRQRKLP EEHARFYSAE 370 380 390 400 410 420 ISLALNYLHE RGIIYRDLKL DNVLLDSEGH IKLTDYGMCK EGLRPGDTTS TFCGTPNYIA 430 440 450 460 470 480 PEILRGEDYG FSVDWWALGV LMFEMMAGRS PFDIVGSSDN PDQNTEDYLF QVILEKQIRI 490 500 510 520 530 540 PRSLSVKAAS VLKSFLNKDP KERLGCHPQT GFADIQGHPF FRNVDWDMME QKQVVPPFKP 550 560 570 580 590 NISGEFGLDN FDSQFTNEPV QLTPDDDDIV RKIDQSEFEG FEYINPLLMS AEECV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A new member of the third class in the protein kinase C family, PKC lambda, expressed dominantly in an undifferentiated mouse embryonal carcinoma cell line and also in many tissues and cells." Akimoto K., Mizuno K., Osada S., Hirai S., Tanuma S., Suzuki K., Ohno S. J. Biol. Chem. 269:12677-12683(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Evidence that atypical protein kinase C-lambda and atypical protein kinase C-zeta participate in Ras-mediated reorganization of the F-actin cytoskeleton." Uberall F., Hellbert K., Kampfer S., Maly K., Villunger A., Spitaler M., Mwanjewe J., Baier-Bitterlich G., Baier G., Grunicke H.H. J. Cell Biol. 144:413-425(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[4]	"The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42." Joberty G., Petersen C., Gao L., Macara I.G. Nat. Cell Biol. 2:531-539(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT OF A COMPLEX CONTAINING PARD6B; PARD3 AND CDC42.
[5]	"Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins." Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., Michaelsen E., Bjoerkoey G., Johansen T. J. Biol. Chem. 278:34568-34581(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SQSTM1 AND MAP2K5, MUTAGENESIS OF ARG-27; VAL-28; LYS-29; TRP-70; ASP-72; GLU-74; ASP-76; GLN-83 AND GLU-85.
[6]	"Insulin-induced GLUT4 translocation involves protein kinase C-lambda-mediated functional coupling between Rab4 and the motor protein kinesin." Imamura T., Huang J., Usui I., Satoh H., Bever J., Olefsky J.M. Mol. Cell. Biol. 23:4892-4900(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"Targeted deletion of protein kinase C lambda reveals a distribution of functions between the two atypical protein kinase C isoforms." Soloff R.S., Katayama C., Lin M.Y., Feramisco J.R., Hedrick S.M. J. Immunol. 173:3250-3260(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[8]	"Protein kinase C-lambda knockout in embryonic stem cells and adipocytes impairs insulin-stimulated glucose transport." Bandyopadhyay G., Standaert M.L., Sajan M.P., Kanoh Y., Miura A., Braun U., Kruse F., Leitges M., Farese R.V. Mol. Endocrinol. 18:373-383(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"Function of atypical protein kinase C lambda in differentiating photoreceptors is required for proper lamination of mouse retina." Koike C., Nishida A., Akimoto K., Nakaya M.A., Noda T., Ohno S., Furukawa T. J. Neurosci. 25:10290-10298(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"Substrate recognition mechanism of atypical protein kinase Cs revealed by the structure of PKCiota in complex with a substrate peptide from Par-3." Wang C., Shang Y., Yu J., Zhang M. Structure 20:791-801(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 231-595 IN COMPLEX WITH RAT PARD3 PEPTIDE, PHOSPHORYLATION AT THR-563, PSEUDOSUBSTRATE MOTIF.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D28577 mRNA. Translation: BAA32499.1. Different initiation.
BC021630 mRNA. Translation: AAH21630.1. Different initiation.

IPI

IPI00121084.

PIR

A53758.

RefSeq

NP_032883.2. NM_008857.3.

UniGene

Mm.291554.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4DC2	X-ray	2.40	A	231-595	[»]

ProteinModelPortal

Q62074.

SMR

Q62074. Positions 25-107, 138-190, 248-587.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-32555N.

IntAct

Q62074. 1 interaction.

PTM databases

PhosphoSite

Q62074.

Proteomic databases

PaxDb

Q62074.

PRIDE

Q62074.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000108249; ENSMUSP00000103884; ENSMUSG00000037643.

GeneID

18759.

KEGG

mmu:18759.

Organism-specific databases

CTD

5584.

MGI

MGI:99260. Prkci.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00700000104096.

HOGENOM

HOG000233033.

HOVERGEN

HBG108317.

InParanoid

Q62074.

KO

K06069.

OMA

RVKAYYK.

OrthoDB

EOG4T782V.

Enzyme and pathway databases

BRENDA

2.7.11.13. 3474.

Gene expression databases

ArrayExpress

Q62074.

Bgee

Q62074.

CleanEx

MM_PRKCI.

Genevestigator

Q62074.

GermOnline

ENSMUSG00000037643. Mus musculus.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR000270. OPR_PB1.
IPR012233. PKC_zeta.
IPR017892. Pkinase_C.
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. 1 hit.
PF00564. PB1. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]

PIRSF

PIRSF000554. PKC_zeta. 1 hit.

PRINTS

PR00008. DAGPEDOMAIN.

SMART

SM00109. C1. 1 hit.
SM00666. PB1. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS51285. AGC_KINASE_CTER. 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. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

294941.

SOURCE

Search...

Entry information

Entry name

KPCI_MOUSE

Accession

Primary (citable) accession number: Q62074

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	June 16, 2009
Last modified:	May 1, 2013
This is version 142 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program