Reviewed, UniProtKB/Swiss-Prot P11802 (CDK4_HUMAN)

Names and origin

Protein names

Recommended name:
    Cell division protein kinase 4
    EC=2.7.11.22
Alternative name(s):
    Cyclin-dependent kinase 4
    PSK-J3

Gene names

Name:

CDK4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	303 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Probably involved in the control of the cell cycle.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Phosphorylation at Thr-172 is necessary for enzymatic activity By similarity.
Subunit structure	Forms a stable complex with D-type G1 cyclins. Interacts with SEI1 and ZNF655/VIK.
Involvement in disease	CDK4 mutations are involved in tumor formation. Defects in CDK4 are the cause of cutaneous malignant melanoma 3 (CMM3) [MIM:609048, 155600]. Malignant melanoma is a malignant neoplasm of melanocytes, arising de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle Cell division
Coding sequence diversity	Polymorphism
Disease	Disease mutation Proto-oncogene
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	G1/S transition of mitotic cell cycle Inferred from mutant phenotype. Source: UniProtKB cell division Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of fibroblast proliferation Inferred from mutant phenotype. Source: UniProtKB protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of gene expression Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cyclin-dependent protein kinase holoenzyme complex Inferred from direct assay. Source: UniProtKB cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro cyclin-dependent protein kinase activity Inferred from electronic annotation. Source: EC protein binding Ref.10 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ACTR3B	Q9P1U1	1	EBI-295644,EBI-1047175
CCND1	P24385	6	EBI-295644,EBI-375001
CCND2	P30279	1	EBI-295644,EBI-748789
CCND3	P30281	3	EBI-295644,EBI-375013
CDC37	Q16543	4	EBI-295644,EBI-295634
CDC7	O00311	1	EBI-295644,EBI-374980
CDKN1A	P38936	2	EBI-295644,EBI-375077
CDKN1B	P46527	2	EBI-295644,EBI-519280
CDKN1C	P49918	1	EBI-295644,EBI-519256
CDKN2A	P42771	5	EBI-295644,EBI-375053
CDKN2B	P42772	2	EBI-295644,EBI-711280
CDKN2C	P42773	1	EBI-295644,EBI-711290
DBNL	Q9UJU6	1	EBI-295644,EBI-751783
GEMIN4	P57678	1	EBI-295644,EBI-356700
LYN	P07948	1	EBI-295644,EBI-79452
MCM2	P49736	1	EBI-295644,EBI-374819
PPP1CA	P62136	1	EBI-295644,EBI-357253
PPP1CC	P36873-1	1	EBI-295644,EBI-356289
RPRM	Q9NS64	1	EBI-295644,EBI-1052363
SMC1A	Q14683	1	EBI-295644,EBI-80690
SMC3	Q9UQE7	1	EBI-295644,EBI-80718
ZNF655	Q8N720	2	EBI-295644,EBI-625509

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 303

303

Cell division protein kinase 4

PRO_0000085778

Regions

Domain

6 – 295

290

Protein kinase

Nucleotide binding

12 – 20

9

ATP By similarity

Compositional bias

42 – 48

7

Poly-Gly

Sites

Active site

140

1

Proton acceptor By similarity

Binding site

35

1

ATP By similarity

Amino acid modifications

Modified residue

172

1

Phosphothreonine; by CAK By similarity

Natural variations

Natural variant

24

1

R → C in CMM3; somatic and familial; generates a dominant oncogene resistant to inhibition by p16(INK4a). dbSNP rs11547328.

VAR_006200

Natural variant

24

1

R → H in CMM3.

VAR_006201

Natural variant

41

1

N → S in CMM3; sporadic.

VAR_021152

Natural variant

82

1

R → Q: dbSNP rs3211612.

VAR_029153

Natural variant

122

1

R → H

VAR_041976

Secondary structure

1

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303

Helix Strand Turn

Details...

Beta strand

7 – 15

9

Beta strand

18 – 25

8

Turn

26 – 29

4

Beta strand

30 – 40

11

Turn

46 – 48

3

Helix

51 – 66

16

Beta strand

74 – 81

8

Beta strand

83 – 94

12

Helix

100 – 104

5

Helix

114 – 133

20

Helix

143 – 145

3

Beta strand

146 – 148

3

Beta strand

154 – 156

3

Beta strand

164 – 166

3

Turn

168 – 170

3

Beta strand

173 – 175

3

Helix

176 – 179

4

Helix

183 – 186

4

Helix

194 – 209

16

Helix

219 – 230

12

Helix

235 – 237

3

Helix

246 – 248

3

Helix

257 – 260

4

Helix

266 – 275

10

Turn

280 – 282

3

Helix

286 – 291

6

Turn

293 – 295

3

Sequences

	Sequence		Length	Mass (Da)
	P11802-1 [UniParc]. Last modified November 1, 1995. Version 2. Checksum: 0916A0C07403A33A	FASTA	303	33,730
	10 20 30 40 50 60 MATSRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGGGGGGLP ISTVREVALL 70 80 90 100 110 120 RRLEAFEHPN VVRLMDVCAT SRTDREIKVT LVFEHVDQDL RTYLDKAPPP GLPAETIKDL 130 140 150 160 170 180 MRQFLRGLDF LHANCIVHRD LKPENILVTS GGTVKLADFG LARIYSYQMA LTPVVVTLWY 190 200 210 220 230 240 RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR 250 260 270 280 290 300 DVSLPRGAFP PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKDEG NPE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Hanks S.K. Submitted (FEB-1987) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 amplification in human cancers." Elkahloun A.G., Krizman D.B., Wang Z., Hofmann T.A., Roe B.A., Meltzer P.S. Genomics 42:295-301(1997) [PubMed: 9192850] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma." Wolfel T., Hauer M., Schneider J., Serrano M., Wolfel C., Klehmann-Hieb E., De Plaen E., Hankeln T., Meyer Zum Bueschenfelde K.-H., Beach D. Science 269:1281-1284(1995) [PubMed: 7652577] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CMM3 CYS-24.
[4]	"Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma." Zuo L., Weger J., Yang Q., Goldstein A.M., Tucker M.A., Walker G.J., Hayward N., Dracopoli N.C. Nat. Genet. 12:97-99(1996) [PubMed: 8528263] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT CMM3 CYS-24.
[5]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Braun A.C., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Muscle.
[7]	"Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family." Hanks S.K. Proc. Natl. Acad. Sci. U.S.A. 84:388-392(1987) [PubMed: 2948189] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 88-188.
[8]	"Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas." Khatib Z.A., Matsushime H., Valentine M., Shapiro D.N., Sherr C.J., Look A.T. Cancer Res. 53:5535-5541(1993) [PubMed: 8221695] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 95-182.
[9]	"Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)." Sugimoto M., Nakamura T., Ohtani N., Hampson L., Hampson I.N., Shimamoto A., Furuichi Y., Okumura K., Niwa S., Taya Y., Hara E. Genes Dev. 13:3027-3033(1999) [PubMed: 10580009] [Abstract] Cited for: INTERACTION WITH SEI1.
[10]	"Characterization of VIK-1: a new Vav-interacting Kruppel-like protein." Houlard M., Romero-Portillo F., Germani A., Depaux A., Regnier-Ricard F., Gisselbrecht S., Varin-Blank N. Oncogene 24:28-38(2005) [PubMed: 15558030] [Abstract] Cited for: INTERACTION WITH ZNF655/VIK.
[11]	"Complete scanning of the CDK4 gene by denaturing gradient gel electrophoresis: a novel missense mutation but low overall frequency of mutations in sporadic metastatic malignant melanoma." Guldberg P., Kirkin A.F., Gronbaek K., thor Straten P., Ahrenkiel V., Zeuthen J. Int. J. Cancer 72:780-783(1997) [PubMed: 9311594] [Abstract] Cited for: VARIANT CMM3 SER-41.
[12]	"Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France." Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B. Hum. Mol. Genet. 7:209-216(1998) [PubMed: 9425228] [Abstract] Cited for: VARIANT CMM3 HIS-24.
[13]	Erratum Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B. Hum. Mol. Genet. 7:941-941(1998)
[14]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] HIS-122.
+	Additional computationally mapped references.

Web resources

GeneReviews

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

M14505 mRNA. Translation: AAA35673.1.
U81031 Genomic DNA. Translation: AAC39521.2.
Z48970 mRNA. Translation: CAA88834.1.
U37022 Genomic DNA. Translation: AAC50506.1.
AF507942 Genomic DNA. Translation: AAM23014.1.
BC003644 mRNA. Translation: AAH03644.1.
BC005864 mRNA. Translation: AAH05864.1.
BC010153 mRNA. Translation: AAH10153.1.
S67448 Genomic DNA. Translation: AAD13991.1.

PIR

I52695.
S52841.

RefSeq

NP_000066.1.

UniGene

Hs.95577

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LD2	model	-	A	1-303	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:24211N.
DIP:875N.

IntAct

P11802.

PTM databases

PhosphoSite

P11802.

Polymorphism databases

NIEHS-SNPs

Search...

Genome annotation databases

Ensembl

ENSG00000135446. Homo sapiens. [Contig view]

GeneID

1019.

KEGG

hsa:1019.

Organism-specific databases

H-InvDB

HIX0010753.

HGNC

HGNC:1773. CDK4.

HPA

CAB015153.

MIM

123829. gene.
155600. phenotype.
609048. phenotype.

Orphanet

618. Melanoma, familial.

PharmGKB

PA102.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P11802.

HOVERGEN

P11802.

Enzyme and pathway databases

Reactome

REACT_152. Cell Cycle, Mitotic.

Gene expression databases

ArrayExpress

P11802.

CleanEx

HS_CDK4.

GermOnline

ENSG00000135446. Homo sapiens.

Family and domain databases

InterPro

IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_bd_CS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

Pfam

PF0