CDK4

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.

CDK4 Related Areas

Cancer>>Cell Cycle>>Cyclin-Dependent Kinase (CDK)>>CDK4

Enzyme>>Protein Kinase>>Intracellular Kinase>>Cyclin-Dependent Kinase (CDK)>>CDK4

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>CDK4

CDK4 Alternative Names

CDK4, CMM3, MGC14458, PSK-J3 [Homo sapiens]
Cdk4, Crk3 [Mus musculus]

Summaries for CDK4

Entrez Gene summary for 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.

OMIM - description for CDK4:

Cyclin-dependent kinase-4 (CDK4) is a protein-serine kinase involved in the cell cycle. Human cell division is regulated primarily at the G1-to-S or the G2-to-M boundaries within the cell cycle. The sequential activation of cyclin-dependent kinases and their subsequent phosphorylation of critical substrates promote orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins (e.g., D1, 168461; D2, 123833; D3, 123834) are involved in the control of cell proliferation during the G1 phase. CDK4 is inhibited by p16, also known as cyclin-dependent kinase inhibitor-2

Wikipedia summary for CDK4:

Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family. 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.[1] It is regulated by Cyclin D.

Human CDK4 Protein General Information

 

• Protein names: Cyclin-dependent kinase 4, Short Name=CD40
• Sequence length: 303 AA.
• Sequence similarities: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.
• 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.
• 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 phosphosphorylation 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.
• 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.
• Involvement in disease: 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.

General information above from UniProt

Function for CDK4 Protein

UniProtKB:

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.

Genatlas:

• protein kinase superfamily
• serine/threonine kinase, involved in cell cycle regulation
• ssential for the G1- to S-phase transition during the cell cycle and its expression is primarily controlled at the transcriptional level
• key regulator of the transition through the G(1) phase of the cell cycle

Homology for human CDK4

• ortholog to yeast S.cerevisiae cdc28

Phenotype Information for CDK4

• Gene/Locus: CDK4, CMM3
• Phenotype: {Melanoma, cutaneous malignant, 3}

Phenotype Information for CDK4 from OMIM (Online Mendelian Inheritance in Man)

Drugs for CDK4

Target	Drug Name	Disease	Drug Status
CDK4	Capridine-beta	Advanced Solid Tumors	Preclinical
CDK4	PD-332991	Various cancers	Phase II
CDK4	Ro 31-7453	Ovarian Cancer; Endometrial Cancer	Phase II
CDK4	P1446A-05	Advanced refractory malignancies	Phase II
CDK4	P276-00	Multiple myeloma	Phase I
CDK4	PD-0332991	Breast Cancer	Phase I

Drugs for CDK4 from TTD (Therapeutic Targets Database)