CDK4
The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported.
Full Name
Cyclin Dependent Kinase 4
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.
Biological Process
Adipose tissue development Source: Ensembl
Animal organ regeneration Source: Ensembl
Cell division Source: UniProtKB-KW
Cellular response to insulin stimulus Source: Ensembl
Cellular response to interleukin-4 Source: Ensembl
Cellular response to ionomycin Source: Ensembl
Cellular response to lipopolysaccharide Source: Ensembl
Cellular response to phorbol 13-acetate 12-myristate Source: Ensembl
Circadian rhythm Source: Ensembl
G1/S transition of mitotic cell cycle Source: BHF-UCL
Granulocyte differentiation Source: Reactome
Lens development in camera-type eye Source: Ensembl
Negative regulation of cell cycle arrest Source: UniProtKB
Negative regulation of G1/S transition of mitotic cell cycle Source: Reactome
Positive regulation of apoptotic process Source: Ensembl
Positive regulation of cell cycle Source: Reactome
Positive regulation of cell population proliferation Source: BHF-UCL
Positive regulation of cell size Source: Ensembl
Positive regulation of fibroblast proliferation Source: BHF-UCL
Positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
Positive regulation of translation Source: Ensembl
Protein phosphorylation Source: BHF-UCL
Regulation of cell cycle Source: GO_Central
Regulation of gene expression Source: BHF-UCL
Regulation of insulin receptor signaling pathway Source: Ensembl
Regulation of lipid biosynthetic process Source: Ensembl
Regulation of lipid catabolic process Source: Ensembl
Regulation of multicellular organism growth Source: Ensembl
Regulation of transcription initiation from RNA polymerase II promoter Source: Reactome
Response to drug Source: UniProtKB
Response to hyperoxia Source: Ensembl
Response to lead ion Source: Ensembl
Response to testosterone Source: Ensembl
Response to toxic substance Source: Ensembl
Signal transduction Source: Ensembl
Cellular Location
Nucleus; Nucleus membrane; Cytoplasm. 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.
Involvement in disease
Melanoma, cutaneous malignant 3 (CMM3): 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.
PTM
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.
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Datasheet