Molecular Target Synopsis
Domains and Structures
Drugs and Clinical Candidates
Ligand Efficiency Plot
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
Germline Genetics

CDK4 (P11802) - Overview - Molecular Target Synopsis


CDK4, Cyclin-dependent kinase 4
Enzyme Classification
UniProt P11802

Also Known as CDK4_HUMAN, 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 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. 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 phosphorylation 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. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (PubMed:27353360).

Inspect Structure
See all 3D Structures for CDK4

Isoforms / Transcripts (Protein Coding)


CDK4 is targeted by Approved Drugs PD0332991, Ribociclib, Ribociclib Succinate. (see details)
Ribociclib Succinate

Sub-cellular localization

UniProt: CDK4 is active in the following subcellular-locations: cytoplasm, membrane, nucleus.
GO terms: CDK4 is active in the following subcellular-locations: bicellular tight junction, chromatin, cyclin D2-CDK4 complex, cyclin-dependent protein kinase holoenzyme complex, cytosol, nuclear membrane, nucleolus, nucleoplasm, nucleus, perinuclear region of cytoplasm, transcription factor complex.

GO terms

Gene Copy Number Variation

In COSMIC - Cell Lines Project CDK4 has gain in 15 cell-lines, loss in 0 cell-lines and no signal in 989 cell-lines. (see details)

Gene Expression

In NCI60, the highest expressing cell lines are: ACHN, SN12C, MALME_3M

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: CAL-120, JIMT-1, NCI-H1792

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HeLa-S3, A549

(see details)

RNA Interference

CDK4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SUM44, MCF12A. (see details)

3D Structures

For CDK4 there are:
9 structures (10 chains) solved
0 are solved in complex with at least one small molecule ligand

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry

CDK4 has been screened with 3007 compounds (3949 bioactivities), 1294 compounds have bioactivities that show binding affinity of <= 500nM (1466 bioactivities). (see details)