3g33

Structural highlights

Disease

[CDK4_HUMAN] Defects in CDK4 are a cause of susceptibility to cutaneous malignant melanoma type 3 (CMM3) [MIM:609048]. Malignant melanoma is 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.^{[1] [2] [3] [4]}

Function

[CDK4_HUMAN] 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 G(1)/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 G(1) phase. Hypophosphorylates RB1 in early G(1) 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.^{[5] [6] [7]} [CCND3_HUMAN] Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH, Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 1995 Sep 1;269(5228):1281-4. PMID:7652577
2. ↑ Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996 Jan;12(1):97-9. PMID:8528263 doi:http://dx.doi.org/10.1038/ng0196-97
3. ↑ Guldberg P, Kirkin AF, Gronbaek K, thor Straten P, Ahrenkiel V, Zeuthen J. 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. Int J Cancer. 1997 Sep 4;72(5):780-3. PMID:9311594
4. ↑ Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J, Bressac-de Paillerets B. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet. 1998 Feb;7(2):209-16. PMID:9425228
5. ↑ Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, Kato J, Segawa K, Yoshida E, Nishimura S, Taya Y. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J. 1996 Dec 16;15(24):7060-9. PMID:9003781
6. ↑ Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004 Jul 8;430(6996):226-31. PMID:15241418 doi:10.1038/nature02650
7. ↑ Wang Z, Xie Y, Zhang L, Zhang H, An X, Wang T, Meng A. Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition. Cell Struct Funct. 2008;33(2):171-83. Epub 2008 Oct 1. PMID:18827403
8. ↑ Liu W, Sun M, Jiang J, Shen X, Sun Q, Liu W, Shen H, Gu J. Cyclin D3 interacts with human activating transcription factor 5 and potentiates its transcription activity. Biochem Biophys Res Commun. 2004 Sep 3;321(4):954-60. PMID:15358120 doi:10.1016/j.bbrc.2004.07.053
9. ↑ Takaki T, Echalier A, Brown NR, Hunt T, Endicott JA, Noble ME. The structure of CDK4/cyclin D3 has implications for models of CDK activation. Proc Natl Acad Sci U S A. 2009 Feb 23. PMID:19237555