Q16667 (CDKN3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase inhibitor 3
EC=3.1.3.16
EC=3.1.3.48

Alternative name(s):
CDK2-associated dual-specificity phosphatase
Cyclin-dependent kinase interactor 1
Cyclin-dependent kinase-interacting protein 2
Kinase-associated phosphatase

Gene names

Name:	CDKN3
Synonyms:	CDI1, CIP2, KAP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	212 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May play a role in cell cycle regulation. Dual specificity phosphatase active toward substrates containing either phosphotyrosine or phosphoserine residues. Dephosphorylates CDK2 at 'Thr-160' in a cyclin-dependent manner. Ref.1 Ref.2 Ref.12
Catalytic activity	Protein tyrosine phosphate + H2O = protein tyrosine + phosphate. A phosphoprotein + H2O = a protein + phosphate.
Subunit structure	Interacts with cyclin-dependent kinases such as CDK1, CDK2 and CDK3. Does not interact with CDK4. Interacts (via C-terminus) with phosphorylated CDK2 (via C-terminal helix). Interacts with MS4A3 (via C-terminus); the interaction enhances CDKN3 enzymatic activity. Ref.1 Ref.2 Ref.4 Ref.14 Ref.15
Subcellular location	Cytoplasm › perinuclear region Ref.13.
Induction	Up-regulated in breast and prostate cancer cells. Ref.13
Involvement in disease	Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Note: The gene represented in this entry may be involved in disease pathogenesis. Ref.3
Sequence similarities	Belongs to the protein-tyrosine phosphatase family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Molecular function	Hydrolase Protein phosphatase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1/S transition of mitotic cell cycle Traceable author statement Ref.2. Source: ProtInc cell cycle arrest Inferred from direct assay Ref.1. Source: MGI negative regulation of cell proliferation Traceable author statement Ref.1. Source: ProtInc regulation of cyclin-dependent protein serine/threonine kinase activity Traceable author statement Ref.1. Source: ProtInc
Cellular_component	perinuclear region of cytoplasm Inferred from direct assay Ref.13. Source: UniProtKB
Molecular_function	protein serine/threonine phosphatase activity Inferred from direct assay Ref.4. Source: MGI protein tyrosine phosphatase activity Inferred from direct assay Ref.1. Source: MGI protein tyrosine/serine/threonine phosphatase activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDK2	P24941	2	EBI-1031527,EBI-375096

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q16667-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q16667-2)

The sequence of this isoform differs from the canonical sequence as follows:
     11-50: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 212

212

Cyclin-dependent kinase inhibitor 3

PRO_0000094949

Regions

Region

1 – 34

34

Interaction with CDK2

Sites

Active site

140

1

By similarity

Natural variations

Alternative sequence

11 – 50

40

Missing in isoform 2.

VSP_036613

Natural variant

31

1

W → R in HCC; patient BX-01. Ref.3

VAR_013842

Natural variant

78

1

F → L in HCC; patient T9. Ref.3

VAR_013843

Natural variant

79

1

C → Y in HCC; patient BX-01. Ref.3

VAR_013844

Natural variant

91

1

N → K in HCC; patient BX-10. Ref.3

VAR_013845

Natural variant

94

1

D → V in HCC; patient NT1. Ref.3

VAR_013846

Natural variant

95

1

L → F in HCC; patient BX-05. Ref.3

VAR_013847

Natural variant

108

1

I → V in HCC; patient T9. Ref.3

VAR_013848

Natural variant

159

1

S → F.
Corresponds to variant rs1803843 [ dbSNP | Ensembl ].

VAR_051769

Natural variant

187

1

N → S in HCC; patient NT4. Ref.3

VAR_013849

Natural variant

195

1

K → I in HCC; patient NT4. Ref.3

VAR_013850

Experimental info

Sequence conflict

2

1

K → E in AAC04932. Ref.1

Sequence conflict

2

1

K → E in AAV38258. Ref.8

Sequence conflict

10

1

S → G in AAK06380. Ref.3

Secondary structure

1

.

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212

Helix Strand Turn

Details...

Beta strand

30 – 33

4

Helix

35 – 37

3

Beta strand

42 – 47

6

Helix

60 – 70

11

Beta strand

74 – 77

4

Helix

81 – 86

6

Helix

92 – 98

7

Beta strand

102 – 105

4

Helix

116 – 131

16

Beta strand

136 – 139

4

Beta strand

141 – 145

5

Helix

146 – 158

13

Beta strand

160 – 162

3

Helix

164 – 175

12

Helix

183 – 189

7

Helix

192 – 197

6

Turn

198 – 200

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: D87FAC8E28F6525F	FASTA	212	23,805
	10 20 30 40 50 60 MKPPSSIQTS EFDSSDEEPI EDEQTPIHIS WLSLSRVNCS QFLGLCALPG CKFKDVRRNV 70 80 90 100 110 120 QKDTEELKSC GIQDIFVFCT RGELSKYRVP NLLDLYQQCG IITHHHPIAD GGTPDIASCC 130 140 150 160 170 180 EIMEELTTCL KNYRKTLIHC YGGLGRSCLV AACLLLYLSD TISPEQAIDS LRDLRGSGAI 190 200 210 QTIKQYNYLH EFRDKLAAHL SSRDSQSRSV SR
	Isoform 2 [UniParc]. Checksum: E1F3AA29AAABE3DE	FASTA	172	19,359
	10 20 30 40 50 60 MKPPSSIQTS CKFKDVRRNV QKDTEELKSC GIQDIFVFCT RGELSKYRVP NLLDLYQQCG 70 80 90 100 110 120 IITHHHPIAD GGTPDIASCC EIMEELTTCL KNYRKTLIHC YGGLGRSCLV AACLLLYLSD 130 140 150 160 170 TISPEQAIDS LRDLRGSGAI QTIKQYNYLH EFRDKLAAHL SSRDSQSRSV SR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2." Gyuris J., Golemis E., Chertkov H., Brent R. Cell 75:791-803(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH CDK1; CDK2 AND CDK3.
[2]	"KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases." Hannon G.J., Casso D., Beach D. Proc. Natl. Acad. Sci. U.S.A. 91:1731-1735(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH CDK1 AND CDK2.
[3]	"Aberrant transcripts of the cyclin-dependent kinase-associated protein phosphatase in hepatocellular carcinoma." Yeh C.-T., Lu S.-C., Chen T.-C., Peng C.-Y., Liaw Y.-F. Cancer Res. 60:4697-4700(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), VARIANTS HCC ARG-31; LEU-78; TYR-79; LYS-91; VAL-94; PHE-95; VAL-108; SER-187 AND ILE-195.
[4]	"Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant." Yeh C.-T., Lu S.-C., Chao C.-H., Chao M.-L. Biochem. Biophys. Res. Commun. 305:311-314(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH CDK2.
[5]	Harper W., Elledge S.J. Submitted (NOV-1993) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]	Schupp I. Submitted (APR-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[7]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[8]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[9]	NIEHS SNPs program Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[10]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[11]	"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] (ISOFORM 2). Tissue: Retinoblastoma.
[12]	"Dephosphorylation of Cdk2 Thr160 by the cyclin-dependent kinase-interacting phosphatase KAP in the absence of cyclin." Poon R.Y.C., Hunter T. Science 270:90-93(1995) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Overexpression of kinase-associated phosphatase (KAP) in breast and prostate cancer and inhibition of the transformed phenotype by antisense KAP expression." Lee S.W., Reimer C.L., Fang L., Iruela-Arispe M.L., Aaronson S.A. Mol. Cell. Biol. 20:1723-1732(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, INDUCTION.
[14]	"Human HTm4 is a hematopoietic cell cycle regulator." Donato J.-L., Ko J., Kutok J.L., Cheng T., Shirakawa T., Mao X.-Q., Beach D., Scadden D.T., Sayegh M.H., Adra C.N. J. Clin. Invest. 109:51-58(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MS4A3.
[15]	"Binding of HTm4 to cyclin-dependent kinase (Cdk)-associated phosphatase (KAP).Cdk2.cyclin A complex enhances the phosphatase activity of KAP, dissociates cyclin A, and facilitates KAP dephosphorylation of Cdk2." Chinami M., Yano Y., Yang X., Salahuddin S., Moriyama K., Shiroishi M., Turner H., Shirakawa T., Adra C.N. J. Biol. Chem. 280:17235-17242(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MS4A3.
[16]	"Phosphoprotein-protein interactions revealed by the crystal structure of kinase-associated phosphatase in complex with phosphoCDK2." Song H., Hanlon N., Brown N.R., Noble M.E.M., Johnson L.N., Barford D. Mol. Cell 7:615-626(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH THR-160 PHOSPHORYLATED CDK2.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U02681 mRNA. Translation: AAC04932.1.
L27711 mRNA. Translation: AAA66496.1.
AF213033 mRNA. Translation: AAK06365.1.
AF213036 mRNA. Translation: AAK06368.1.
AF213038 mRNA. Translation: AAK06370.1.
AF213039 mRNA. Translation: AAK06371.1.
AF213041 mRNA. Translation: AAK06373.1.
AF213042 mRNA. Translation: AAK06374.1.
AF213046 mRNA. Translation: AAK06377.1.
AF213047 mRNA. Translation: AAK06378.1.
AF213049 mRNA. Translation: AAK06380.1.
AF213053 mRNA. Translation: AAK06384.1.
AY257474 mRNA. Translation: AAP13062.1.
L25876 mRNA. Translation: AAA60222.1.
EF560750 mRNA. Translation: ABQ59060.1.
CR407666 mRNA. Translation: CAG28594.1.
BT019451 mRNA. Translation: AAV38258.1.
AY194117 Genomic DNA. Translation: AAN86348.1.
CH471061 Genomic DNA. Translation: EAW80632.1.
CH471061 Genomic DNA. Translation: EAW80634.1.
BC064965 mRNA. Translation: AAH64965.1.

IPI

IPI00003445.
IPI00909462.

PIR

A49436.

RefSeq

NP_001124323.1. NM_001130851.1.
NP_005183.2. NM_005192.3.

UniGene

Hs.84113.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FPZ	X-ray	2.00	A/B/C/D/E/F	1-212	[»]
1FQ1	X-ray	3.00	A	1-212	[»]

ProteinModelPortal

Q16667.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24231N.
DIP-245N.

IntAct

Q16667. 1 interaction.

MINT

MINT-204916.

PTM databases

PhosphoSite

Q16667.

Polymorphism databases

DMDM

2499769.

Proteomic databases

PaxDb

Q16667.

PRIDE

Q16667.

Protocols and materials databases

DNASU

1033.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000335183; ENSP00000335357; ENSG00000100526.
ENST00000442975; ENSP00000415333; ENSG00000100526.

GeneID

1033.

KEGG

hsa:1033.

UCSC

uc001xap.3. human.
uc001xar.3. human.

Organism-specific databases

CTD

1033.

GeneCards

GC14P054863.

HGNC

HGNC:1791. CDKN3.

HPA

CAB005285.

MIM

114550. phenotype.
123832. gene.

neXtProt

NX_Q16667.

PharmGKB

PA26324.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG2453.

HOVERGEN

HBG075798.

InParanoid

Q16667.

KO

K14167.

OMA

QYGIITH.

OrthoDB

EOG49W2GK.

PhylomeDB

Q16667.

Gene expression databases

ArrayExpress

Q16667.

Bgee

Q16667.

Genevestigator

Q16667.

GermOnline

ENSG00000100526. Homo sapiens.

Family and domain databases

InterPro

IPR008425. CDK_inhib_3.
IPR022778. CDKN3.
IPR000387. Tyr/Dual-sp_Pase.
[Graphical view]

Pfam

PF05706. CDKN3. 1 hit.
[Graphical view]

PIRSF

PIRSF037322. CDKN3. 1 hit.

PROSITE

PS00383. TYR_PHOSPHATASE_1. False negative.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q16667.

GenomeRNAi

1033.

NextBio

4349.

SOURCE

Search...

Entry information

Entry name

CDKN3_HUMAN

Accession

Primary (citable) accession number: Q16667
Secondary accession number(s): Q53ZU6 , Q5U0M4, Q6P1N8, Q99585, Q9BPW7, Q9BY36, Q9C042, Q9C046, Q9C047, Q9C049, Q9C051, Q9C053

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.