P11802 (CDK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 4
EC=2.7.11.22

Alternative name(s):
Cell division protein kinase 4
PSK-J3

Gene names

Name:

CDK4

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	303 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Ref.12 Ref.15 Ref.18
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.13 Ref.19 Ref.23
Enzyme regulation	Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequennt activation. Ref.20
Subunit structure	Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Ref.13 Ref.14 Ref.16 Ref.17 Ref.18 Ref.19
Subcellular location	Cytoplasm. Nucleus. Membrane. Note: Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress through G1 phase. The complex accumulates on the nuclear membrane and enters the nucleus on transition from G1 to S phase. Also present in nucleoli and heterochromatin lumps. Colocalizes with RB1 after release into the nucleus. Ref.13 Ref.18
Post-translational modification	Phosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T-loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B. Ref.17 Ref.19 Ref.20 Ref.23 Ref.24
Involvement in disease	Cutaneous malignant melanoma 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.3 Ref.4 Ref.25 Ref.26
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
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Traceable author statement. Source: Reactome G1/S transition of mitotic cell cycle Inferred from mutant phenotype PubMed 7603984. Source: BHF-UCL S phase of mitotic cell cycle Traceable author statement. Source: Reactome cell division Inferred from electronic annotation. Source: UniProtKB-KW circadian rhythm Inferred from electronic annotation. Source: Compara organ regeneration Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of cell size Inferred from electronic annotation. Source: Compara positive regulation of fibroblast proliferation Inferred from mutant phenotype PubMed 17420273. Source: BHF-UCL positive regulation of translation Inferred from electronic annotation. Source: Compara regulation of cell cycle Inferred from electronic annotation. Source: Compara regulation of gene expression Inferred from mutant phenotype PubMed 17420273. Source: BHF-UCL response to drug Inferred from genetic interaction PubMed 18291362. Source: UniProtKB response to hyperoxia Inferred from electronic annotation. Source: Compara response to lead ion Inferred from electronic annotation. Source: Compara response to testosterone stimulus Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara signal transduction Inferred from electronic annotation. Source: Compara
Cellular_component	chromatin Inferred from direct assay Ref.18. Source: UniProtKB cyclin-dependent protein kinase holoenzyme complex Inferred from direct assay Ref.18. Source: UniProtKB cytosol Inferred from direct assay Ref.18. Source: UniProtKB nuclear membrane Inferred from direct assay Ref.18. Source: UniProtKB nucleolus Inferred from direct assay Ref.18. Source: UniProtKB nucleoplasm Traceable author statement. Source: Reactome perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara tight junction Inferred from electronic annotation. Source: Compara transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 8114739. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCND1	P24385	10	EBI-295644,EBI-375001
CCND3	P30281	6	EBI-295644,EBI-375013
CDC37	Q16543	5	EBI-295644,EBI-295634
CDKN1A	P38936	4	EBI-295644,EBI-375077
CDKN1B	P46527	2	EBI-295644,EBI-519280
CDKN2A	P42771	8	EBI-295644,EBI-375053
CDKN2B	P42772	4	EBI-295644,EBI-711280
HSP90AB1	P08238	3	EBI-295644,EBI-352572
MYC	P01106	2	EBI-295644,EBI-447544
RBL1	P28749	2	EBI-295644,EBI-971402
ZNF655	Q8N720	3	EBI-295644,EBI-625509

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 303

303

Cyclin-dependent kinase 4

PRO_0000085778

Regions

Domain

6 – 295

290

Protein kinase

Nucleotide binding

12 – 20

9

ATP By similarity

Region

50 – 56

7

Required for binding D-type cyclins

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 Ref.17 Ref.20 Ref.21 Ref.23 Ref.24

Natural variations

Natural variant

24

1

R → C in CMM3; somatic and familial; generates a dominant oncogene resistant to inhibition by p16(INK4a). Ref.3 Ref.4
Corresponds to variant rs11547328 [ dbSNP | Ensembl ].

VAR_006200

Natural variant

24

1

R → H in CMM3. Ref.26

VAR_006201

Natural variant

41

1

N → S in CMM3; sporadic. Ref.25

VAR_021152

Natural variant

82

1

R → Q. Ref.5
Corresponds to variant rs3211612 [ dbSNP | Ensembl ].

VAR_029153

Natural variant

122

1

R → H. Ref.28
Corresponds to variant rs34386532 [ dbSNP | Ensembl ].

VAR_041976

Experimental info

Mutagenesis

172

1

T → A: Weak enzyme activity towards RB1, but no effect on binding of CCDN1 nor CCDN3. Ref.17

Mutagenesis

172

1

T → E: Retains moderate enzyme activity. Ref.17

Mutagenesis

173

1

P → S: No effect on in vitro phosphorylation by CDK7. Greatly reduced T-172 phosphorylation and enzyme activity. Ref.20

Secondary structure

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303

Helix Strand Turn

Details...

Beta strand

7 – 13

7

Beta strand

15 – 17

3

Beta strand

20 – 24

5

Turn

26 – 28

3

Beta strand

31 – 40

10

Helix

51 – 63

13

Helix

64 – 66

3

Beta strand

74 – 82

9

Beta strand

84 – 94

11

Beta strand

97 – 99

3

Helix

100 – 105

6

Turn

109 – 111

3

Helix

114 – 133

20

Turn

143 – 145

3

Beta strand

146 – 148

3

Turn

150 – 152

3

Beta strand

154 – 156

3

Helix

162 – 169

8

Helix

172 – 175

4

Turn

183 – 185

3

Beta strand

186 – 189

4

Helix

195 – 208

14

Beta strand

209 – 211

3

Helix

219 – 230

12

Turn

235 – 237

3

Beta strand

242 – 244

3

Helix

246 – 248

3

Helix

257 – 260

4

Helix

266 – 275

10

Helix

280 – 282

3

Helix

286 – 290

5

Sequences

	Sequence		Length	Mass (Da)
	P11802 [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CMM3 CYS-24, CHARACTERIZATION OF VARIANT 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT CMM3 CYS-24, CHARACTERIZATION OF VARIANT CYS-24.
[5]	NIEHS SNPs program Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-82.
[6]	"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 (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	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].
[9]	"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]. Tissue: Muscle.
[10]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 88-188.
[11]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 95-182.
[12]	"The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2." Kitagawa M., Higashi H., Jung H.K., Suzuki-Takahashi I., Ikeda M., Tamai K., Kato J., Segawa K., Yoshida E., Nishimura S., Taya Y. EMBO J. 15:7060-7069(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"New functional activities for the p21 family of CDK inhibitors." LaBaer J., Garrett M.D., Stevenson L.F., Slingerland J.M., Sandhu C., Chou H.S., Fattaey A., Harlow E. Genes Dev. 11:847-862(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDKN1A; CCND1 AND CCND3, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY.
[14]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SEI1.
[15]	"Cyclin-dependent kinases regulate the antiproliferative function of Smads." Matsuura I., Denissova N.G., Wang G., He D., Long J., Liu F. Nature 430:226-231(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[16]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZNF655.
[17]	"Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK 'inhibitors'." Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E., de Launoit Y., Roger P.P., Coulonval K. Mol. Cell. Biol. 26:5070-5085(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-172, INTERACTION WITH CCND1; CCND3; CDKN2A AND CDKN1B, MUTAGENESIS OF THR-172.
[18]	"Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition." Wang Z., Xie Y., Zhang L., Zhang H., An X., Wang T., Meng A. Cell Struct. Funct. 33:171-183(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION, INTERACTION WITH CCND2.
[19]	"p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes." Ray A., James M.K., Larochelle S., Fisher R.P., Blain S.W. Mol. Cell. Biol. 29:986-999(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDKN1B, PHOSPHORYLATION, CATALYTIC ACTIVITY.
[20]	"Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation." Bockstaele L., Bisteau X., Paternot S., Roger P.P. Mol. Cell. Biol. 29:4188-4200(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-172, ENZYME REGULATION, MUTAGENESIS OF PRO-173.
[21]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-172, MASS SPECTROMETRY.
[22]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[23]	"Crystal structure of human CDK4 in complex with a D-type cyclin." Day P.J., Cleasby A., Tickle I.J., O'Reilly M., Coyle J.E., Holding F.P., McMenamin R.L., Yon J., Chopra R., Lengauer C., Jhoti H. Proc. Natl. Acad. Sci. U.S.A. 106:4166-4170(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF THR-172-PHOSPHORYLATED WILD TYPE AND MUTANTS ALA-172; PHE-172 AND ASP-172 IN COMPLEX WITH CCND1, MASS SPECTROMETRY, PHOSPHORYLATION AT THR-172, CATALYTIC ACTIVITY.
[24]	"The structure of CDK4/cyclin D3 has implications for models of CDK activation." Takaki T., Echalier A., Brown N.R., Hunt T., Endicott J.A., Noble M.E. Proc. Natl. Acad. Sci. U.S.A. 106:4171-4176(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF NONPHOSPHORYLATED FORM IN COMPLEX WITH CCND3, PHOSPHORYLATION AT THR-172, MASS SPECTROMETRY.
[25]	"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] [Europe PMC] [Abstract] Cited for: VARIANT CMM3 SER-41.
[26]	"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] [Europe PMC] [Abstract] Cited for: VARIANT CMM3 HIS-24.
[27]	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)
[28]	"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] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] HIS-122.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.
CR407668 mRNA. Translation: CAG28596.1.
CR542247 mRNA. Translation: CAG47043.1.
AC025165 Genomic DNA. No translation available.
CH471054 Genomic DNA. Translation: EAW97058.1.
BC003644 mRNA. Translation: AAH03644.1.
BC005864 mRNA. Translation: AAH05864.1.
BC010153 mRNA. Translation: AAH10153.1.
S67448 Genomic DNA. Translation: AAD13991.1.

IPI

IPI00007811.

PIR

I52695.
S52841.

RefSeq

NP_000066.1. NM_000075.3.

UniGene

Hs.95577.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LD2	model	-	A	1-303	[»]
2W96	X-ray	2.30	B	1-303	[»]
2W99	X-ray	2.80	B	1-303	[»]
2W9F	X-ray	2.85	B	1-303	[»]
2W9Z	X-ray	2.45	B	1-303	[»]
3G33	X-ray	3.00	A/C	1-303	[»]

ProteinModelPortal

P11802.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24211N.
DIP-875N.

IntAct

P11802. 56 interactions.

MINT

MINT-1201237.

STRING

9606.ENSP00000257904.

PTM databases

PhosphoSite

P11802.

Polymorphism databases

DMDM

1168867.

Proteomic databases

PaxDb

P11802.

PRIDE

P11802.

Protocols and materials databases

DNASU

1019.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000257904; ENSP00000257904; ENSG00000135446.

GeneID

1019.

KEGG

hsa:1019.

UCSC

uc001spv.3. human.

Organism-specific databases

CTD

1019.

GeneCards

GC12M058142.

HGNC

HGNC:1773. CDK4.

HPA

CAB015153.

MIM

123829. gene.
609048. phenotype.

neXtProt

NX_P11802.

Orphanet

618. Familial melanoma.

PharmGKB

PA102.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233024.

HOVERGEN

HBG014652.

InParanoid

P11802.

KO

K02089.

OMA

ARIYSCH.

OrthoDB

EOG4NGGN6.

PhylomeDB

P11802.

Enzyme and pathway databases

BRENDA

2.7.11.22. 2681.

Pathway_Interaction_DB

nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
foxm1pathway. FOXM1 transcription factor network.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.

Reactome

REACT_111183. Meiosis.
REACT_115566. Cell Cycle.

Gene expression databases

ArrayExpress

P11802.

Bgee

P11802.

CleanEx

HS_CDK4.

Genevestigator

P11802.

GermOnline

ENSG00000135446. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
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

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P11802.

ChEMBL

CHEMBL331.

ChiTaRS

Cdk4. human.

EvolutionaryTrace

P11802.

GenomeRNAi

1019.

NextBio

4283.

SOURCE

Search...

Entry information

Entry name

CDK4_HUMAN

Accession

Primary (citable) accession number: P11802
Secondary accession number(s): O00576, Q6FG61

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	November 1, 1995
Last modified:	May 1, 2013
This is version 164 of the entry and version 2 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.