CDK4

CDK4 (cyclin-dependent kinase 4) is a 303-residue serine/threonine protein kinase of the CMGC group, CDC2/CDKX subfamily (EC 2.7.11.22), and the catalytic subunit of the cyclin D-CDK4 holoenzyme. It is catalytically inactive as a monomer and is activated by binding a D-type cyclin (CCND1, CCND2 or CCND3) together with phosphorylation of the activation-loop residue Thr172; activity is opposed by the INK4 inhibitors (p16/CDKN2A, p15/CDKN2B, p18/CDKN2C, p19/CDKN2D) and modulated by the CIP/KIP proteins (p21/CDKN1A, p27/CDKN1B, p57/CDKN1C), which both promote complex assembly and, at higher stoichiometry, inhibit. Before assembly CDK4 is chaperoned by Hsp90-Cdc37. In early-to-mid G1 the cyclin D-CDK4 complex phosphorylates the retinoblastoma-family pocket proteins RB1/pRb, RBL1/p107 and RBL2/p130, relieving their repression of E2F transcription factors and thereby licensing E2F-dependent gene expression and the G1/S transition; cyclin E-CDK2 subsequently completes RB hyperphosphorylation. Additional substrates include SMAD3, FOXM1 and RUNX2. CDK4 is cytoplasmic when uncomplexed; the cyclin D-CDK4 complex assembles in the cytoplasm, accumulates at the nuclear membrane and translocates into the nucleus at the G1/S transition, where it colocalizes with RB1, and is also detected in nucleoli and heterochromatin. Together with its paralog CDK6, CDK4 is the dedicated metazoan G1 cyclin-dependent kinase. It is a major oncology drug target: CDK4 amplification and activating mutations occur in cancer, the germline R24C variant causes familial melanoma, loss-of-function variants cause autosomal-recessive primary microcephaly, and CDK4/6 inhibitors are established therapies in HR-positive breast cancer.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.