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 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.

Classification

Family (Pfam)

PF00069 Pkinase

InterPro

CDK, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 15

• 2W96 X-ray 2.30A
• 2W99 X-ray 2.80A
• 2W9F X-ray 2.85A
• 2W9Z X-ray 2.45A
• 3G33 X-ray 3.00A
• 5FWK EM 3.90A
• 5FWL EM 9.00A
• 5FWM EM 8.00A
• 5FWP EM 7.20A
• 6P8E X-ray 2.30A
• 6P8F X-ray 2.89A
• 6P8G X-ray 2.80A
• … and 3 more

A predicted model is available from AlphaFold.

Gene Ontology · 28

• GO:0005923 bicellular tight junction
• GO:0000785 chromatin
• GO:0097128 cyclin D1-CDK4 complex
• GO:0097129 cyclin D2-CDK4 complex
• GO:0000307 cyclin-dependent protein kinase holoenzyme complex
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0031965 nuclear membrane
• GO:0005730 nucleolus
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005667 transcription regulator complex
• GO:0005524 ATP binding
• GO:0030332 cyclin binding
• GO:0004693 cyclin-dependent protein serine/threonine kinase activity
• GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity
• GO:0106310 protein serine kinase activity
• GO:0051301 cell division
• GO:0000082 G1/S transition of mitotic cell cycle
• GO:0000086 G2/M transition of mitotic cell cycle
• GO:0008284 positive regulation of cell population proliferation
• GO:0048146 positive regulation of fibroblast proliferation
• GO:0010971 positive regulation of G2/M transition of mitotic cell cycle
• GO:0051726 regulation of cell cycle
• GO:0010468 regulation of gene expression
• GO:0060260 regulation of transcription initiation by RNA polymerase II
• GO:0009410 response to xenobiotic stimulus
• GO:0007165 signal transduction

Disease associations

• melanoma, cutaneous malignant, susceptibility to, 3 MONDO:0012183

Drugs targeting this protein · 18

• PHA-793887 inhibitor
• PALBOCICLIB inhibitor
• ABEMACICLIB inhibitor
• RGB-286638 inhibitor
• RIBOCICLIB inhibitor
• RIVICICLIB inhibitor
• AG-24322 inhibitor
• RIBOCICLIB SUCCINATE inhibitor
• RG-547 inhibitor
• TRILACICLIB inhibitor
• VORUCICLIB inhibitor
• ALVOCIDIB inhibitor
• RONICICLIB inhibitor
• AT-7519 inhibitor
• TRILACICLIB DIHYDROCHLORIDE inhibitor
• AZD-5438 inhibitor
• MILCICLIB inhibitor
• UCN-01 inhibitor

Related proteins · sequence + function similarity

• Cyclin-dependent kinase 4 1.00
• Cyclin-dependent kinase 4 0.99
• Cyclin-dependent kinase 4 0.99
• Cyclin-dependent kinase 4 0.99
• Cyclin-dependent kinase 4 0.99
• Cyclin-dependent kinase 6 0.89
• Cell division protein kinase 2 homolog CRK1 0.89
• Cell division control protein 2 homolog 1 0.88
• Cell division control protein 2 homolog C 0.88
• Cyclin-dependent kinase 4 0.87
• Cell division control protein 2 homolog 2 0.87
• Cyclin-dependent kinase 6 0.87

Co-cited proteins · studied together in the literature

• G1/S-specific cyclin-D1 5 shared papers
• Phosphorylase b kinase gamma catalytic chain, liver/testis isoform 1 shared papers
• G1/S-specific cyclin-D3 3 shared papers
• Cyclin-dependent kinase inhibitor 2A 2 shared papers
• G1/S-specific cyclin-D2 1 shared papers
• Transmembrane 4 L6 family member 5 1 shared papers
• Serine/threonine-protein kinase H1 1 shared papers
• Tetraspanin-31 1 shared papers
• Cyclin-dependent kinase inhibitor 1B 2 shared papers
• SERTA domain-containing protein 1 1 shared papers
• Zinc finger protein 655 1 shared papers
• Cyclin-dependent kinase 4 2 shared papers

Literature · 30 cited papers

• Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J. · 2017
• The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat. Commun. · 2016
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression and RhoA activity. Biochim. Biophys. Acta · 2010
• 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. Mol. Cell. Biol. · 2009
• Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal. Chem. · 2009
• Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
• Crystal structure of human CDK4 in complex with a D-type cyclin. Proc. Natl. Acad. Sci. U.S.A. · 2009
• The structure of CDK4/cyclin D3 has implications for models of CDK activation. Proc. Natl. Acad. Sci. U.S.A. · 2009
• Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest. J. Biol. Chem. · 2009
• p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes. Mol. Cell. Biol. · 2009
• Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition. Cell Struct. Funct. · 2008
• … and 18 more in the literature graph