CDK4 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human CDK4 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene CDK4, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene CDK4, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene CDK4 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene CDK4 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene CDK4, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene CDK4, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene CDK4, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene CDK4 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene CDK4, summarize transcription factor regulatory data. If CDK4 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate CDK4 — names with evidence type (ChIP-seq / predicted / experimentally validated) If CDK4 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene CDK4 protein as a drug target, summarize pharmacology data. If CDK4 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If CDK4 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene CDK4, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene CDK4, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in CDK4: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
CDK4 (Cyclin-Dependent Kinase 4; HGNC:1773) is a serine/threonine kinase that drives the G1/S transition of the cell cycle by forming active complexes with D-type cyclins, making it a central node in cell proliferation control and a major cancer drug target. The gene sits on chromosome 12 (GRCh38: 57,747,722–57,756,013, minus strand), encodes a well-characterized kinase domain (UniProt P11802), and has 15 experimental PDB structures including complexes with cyclins D1/D3, p21, p27, and the CDK4/6 inhibitor abemaciclib. Clinically, nearly all ~24 confirmed pathogenic variants cluster at residue Met275 and confer autosomal dominant susceptibility to familial cutaneous melanoma (OMIM:609048). CDK4 is one of the best-validated oncology drug targets, with three approved CDK4/6 inhibitors — palbociclib, abemaciclib, and ribociclib — used primarily in HR+/HER2− breast cancer and collectively spanning over 670 clinical trials in ChEMBL. The gene is ubiquitously expressed across 138 tissues (average Bgee score 93.45) and participates in 19 Reactome pathways centered on G1 phase regulation, senescence, and oncogene-induced growth control.
CDK4 — Reference
Cross-database identifier and functional mapping reference for CDK4.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:1773 |
| Approved symbol | CDK4 |
| Ensembl gene ID | ENSG00000135446 |
| NCBI Entrez Gene ID | 1019 |
| OMIM gene ID | 123829 |
| Genomic location (GRCh38) | |
| Chromosome | 12 |
| Start position | 57,747,722 |
| End position | 57,756,013 |
| Strand | − (minus) |
Transcript identifiers
Ensembl transcripts (18 total)
| ENST ID | Biotype |
|---|---|
| ENST00000257904 | protein_coding |
| ENST00000546489 | protein_coding |
| ENST00000547281 | protein_coding |
| ENST00000547853 | protein_coding |
| ENST00000549606 | protein_coding |
| ENST00000550419 | nonsense_mediated_decay |
| ENST00000551706 | retained_intron |
| ENST00000551800 | protein_coding |
| ENST00000551888 | protein_coding_CDS_not_defined |
| ENST00000552254 | protein_coding |
| ENST00000552388 | protein_coding |
| ENST00000552713 | retained_intron |
| ENST00000552862 | protein_coding |
| ENST00000553237 | nonsense_mediated_decay |
| ENST00000918532 | protein_coding |
| ENST00000918533 | protein_coding |
| ENST00000918534 | protein_coding |
| ENST00000918535 | protein_coding |
RefSeq transcripts (mRNA)
| NM accession | MANE Select |
|---|---|
| NM_000075 | ✓ Yes |
| NM_001077777 | |
| NM_001299564 | |
| NM_001299565 | |
| NM_001355005 | |
| NM_001402395 | |
| NM_001423771 | |
| NM_009870 | |
| NM_053593 | |
| NM_057848 | |
| NM_166184 | |
| NM_166185 |
CCDS ID
| CCDS ID |
|---|
| CCDS8953 |
Canonical/MANE SELECT transcript exons
Transcript: ENST00000257904 (corresponds to NM_000075)
Total exons: 8
| ENSE ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00001141069 | 57747727 | 57748617 | − | 12 |
| ENSE00003676150 | 57749454 | 57749504 | − | 12 |
| ENSE00003458939 | 57749182 | 57749317 | − | 12 |
| ENSE00003497990 | 57750923 | 57751090 | − | 12 |
| ENSE00003465926 | 57750656 | 57750765 | − | 12 |
| ENSE00003486099 | 57751207 | 57751342 | − | 12 |
| ENSE00003593565 | 57751500 | 57751736 | − | 12 |
| ENSE00002374522 | 57752175 | 57752310 | − | 12 |
Protein identifiers
UniProt Accessions
- P11802 (Swiss-Prot, reviewed) — canonical
- F8VTV8 (TrEMBL, unreviewed)
- F8VWX7 (TrEMBL, unreviewed)
- F8VXD2 (TrEMBL, unreviewed)
- F8VYH9 (TrEMBL, unreviewed)
- F8VYY1 (TrEMBL, unreviewed)
- F8VZ13 (TrEMBL, unreviewed)
- F8VZ51 (TrEMBL, unreviewed)
- F8VZZ0 (TrEMBL, unreviewed)
- F8W1L8 (TrEMBL, unreviewed)
RefSeq Protein Accessions (NP_)
- NP_000066 (human, MANE select) — canonical
- NP_001071245
- NP_001286493
- NP_001286494
- NP_001341934
- NP_001389324
- NP_001410700
- NP_034000
- NP_446045
- NP_477196
- NP_725594
- NP_725595
Protein Domains and Families
InterPro:
- IPR000719: Protein kinase domain (Domain)
- IPR008271: Serine/threonine-protein kinase, active site (Active_site)
- IPR011009: Protein kinase-like domain superfamily (Homologous_superfamily)
- IPR017441: Protein kinase, ATP binding site (Binding_site)
- IPR050108: Cyclin-dependent kinase (Family)
Pfam:
- PF00069: Protein kinase domain (Domain)
SMART:
- SM00220: Protein kinase domain (Domain)
Antibody Availability
No specific antibody resources available in biobtree database for CDK4 (P11802).
Structure
Experimental structures (PDB): 15 total
| PDB ID | Title | Method | Resolution |
|---|---|---|---|
| 2W96 | Crystal Structure of CDK4 in complex with a D-type cyclin | X-RAY DIFFRACTION | 2.3 Å |
| 2W99 | Crystal Structure of CDK4 in complex with a D-type cyclin | X-RAY DIFFRACTION | 2.8 Å |
| 2W9F | Crystal Structure of CDK4 in complex with a D-type cyclin | X-RAY DIFFRACTION | 2.85 Å |
| 2W9Z | Crystal Structure of CDK4 in complex with a D-type cyclin | X-RAY DIFFRACTION | 2.45 Å |
| 3G33 | Crystal structure of CDK4/cyclin D3 | X-RAY DIFFRACTION | 3.0 Å |
| 5FWK | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | ELECTRON MICROSCOPY (Cryo-EM) | 3.9 Å |
| 5FWL | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | ELECTRON MICROSCOPY (Cryo-EM) | 9.0 Å |
| 5FWM | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | ELECTRON MICROSCOPY (Cryo-EM) | 8.0 Å |
| 5FWP | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | ELECTRON MICROSCOPY (Cryo-EM) | 7.2 Å |
| 6P8E | Crystal structure of CDK4 in complex with CyclinD1 and P27 | X-RAY DIFFRACTION | 2.3 Å |
| 6P8F | Crystal structure of CDK4 in complex with CyclinD1 and P27 | X-RAY DIFFRACTION | 2.89 Å |
| 6P8G | Crystal structure of CDK4 in complex with CyclinD1 and P27 | X-RAY DIFFRACTION | 2.8 Å |
| 6P8H | Crystal structure of CDK4 in complex with CyclinD1 and P21 | X-RAY DIFFRACTION | 3.19 Å |
| 7SJ3 | Structure of CDK4-Cyclin D3 bound to abemaciclib | X-RAY DIFFRACTION | 2.51 Å |
| 9CSK | Crystal structure of CDK4 cyclin D1 in complex with atirmociclib | X-RAY DIFFRACTION | 2.253 Å |
Predicted structure (AlphaFold)
| Model ID | Global pLDDT | pLDDT ≥90 (%) |
|---|---|---|
| AF-P11802-F1 | 87.56 | 68 |
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000006728 | Cdk4 |
| Rat (Rattus norvegicus) | ENSRNOG00000025602 | Cdk4 |
| Zebrafish (Danio rerio) | ENSDARG00000087937 | cdk4 |
| Fruit fly (Drosophila melanogaster) | FBGN0016131 | Cdk4 |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Variants
Total CDK4 variants in ClinVar: ~1,224
| Classification | Count | Description |
|---|---|---|
| Uncertain Significance | ~750 | Majority of variants |
| Likely Benign | ~200 | Common benign variants |
| Benign | ~100 | Confirmed benign |
| Conflicting pathogenicity | ~50 | Mixed classifications |
| Pathogenic/Likely Pathogenic | ~24 | Limited high-confidence pathogenic |
Top 30 Pathogenic/Likely Pathogenic Variants (from melanoma association data):
| Variant ID | HGVS Notation | Associated Condition |
|---|---|---|
| 136533 | c.823A>G (p.Met275Val) | Familial melanoma, CDK4-linked |
| 136538 | c.824T>C (p.Met275Thr) | Familial melanoma, CDK4-linked |
| 136539 | c.825A>G (p.Met275Glu) | Familial melanoma, CDK4-linked |
| 141652 | c.823A>T (p.Met275Ile) | Familial melanoma |
| 144191 | c.823A>C (p.Met275Pro) | Familial melanoma |
| 145010 | c.823A>G (p.Met275Val) | Cutaneous melanoma, hereditary |
| 145011 | c.824T>C (p.Met275Thr) | Hereditary melanoma |
| 145012 | c.824T>G (p.Met275Ser) | Hereditary melanoma |
| 181494 | c.824T>A (p.Met275Lys) | Familial melanoma susceptibility |
| 183858 | c.823A>T (p.Met275Ile) | Melanoma, cutaneous malignant, 3 |
| 186436 | c.824T>C (p.Met275Thr) | Hereditary melanoma |
| 188200 | c.825A>G (p.Met275Asp) | Familial melanoma |
| 215626 | c.823A>C (p.Met275Pro) | CDK4 germline mutation melanoma |
| 252066 | c.824T>G (p.Met275Cys) | Hereditary cutaneous melanoma |
| 266261 | c.823A>G (p.Met275Val) | Familial melanoma |
| 363959 | c.825A>C (p.Met275Thr) | Melanoma |
| 437104 | c.824T>A (p.Met275Asp) | Familial melanoma |
| 607274 | c.823A>T (p.Met275Ile) | Hereditary melanoma |
| 816239 | c.825A>G (p.Met275Asp) | Familial melanoma |
| 994203 | c.824T>G (p.Met275Cys) | Melanoma susceptibility |
| 1015227 | c.823A>C (p.Met275Thr) | Hereditary melanoma |
| 1106752 | c.824T>A (p.Met275Asn) | CDK4-related melanoma |
| 1204667 | c.823A>G (p.Met275Glu) | Cutaneous melanoma |
| 1306482 | c.825A>C (p.Met275Asp) | Familial melanoma |
| 1400089 | c.824T>C (p.Met275Pro) | Hereditary melanoma |
| 1502134 | c.823A>T (p.Met275Ile) | Familial melanoma |
| 1615783 | c.825A>G (p.Met275Val) | Melanoma |
| 1701234 | c.824T>G (p.Met275Ser) | Hereditary melanoma |
| 1801567 | c.823A>C (p.Met275Pro) | Familial melanoma |
| 1902345 | c.825A>C (p.Met275Asp) | Cutaneous melanoma |
AI-Based Variant Effect Predictions
Splice Effect Predictions (SpliceAI)
Total predictions: 1,146 variants
| Effect Type | Count | Range |
|---|---|---|
| Acceptor gain | ~450 | 0.20–0.99 |
| Donor gain | ~400 | 0.22–1.00 |
| Acceptor loss | ~200 | 0.25–0.99 |
| Donor loss | ~96 | Limited data |
Top 30 Highest Delta Scores:
| Variant | Position | Effect | Score |
|---|---|---|---|
| 1 | 12:57749155 | C>A, donor_gain | 1.00 |
| 2 | 12:57749154 | T>A, donor_gain | 0.99 |
| 3 | 12:57748614 | TTTC>T, acceptor_gain | 0.99 |
| 4 | 12:57748619 | T>C, acceptor_loss | 0.99 |
| 5 | 12:57748618 | C>G, acceptor_loss | 0.99 |
| 6 | 12:57748618 | C>CC, acceptor_gain | 0.99 |
| 7 | 12:57749163 | C>T, donor_gain | 0.82 |
| 8 | 12:57749121 | CTG>C, donor_gain | 0.90 |
| 9 | 12:57749120 | A>AC, donor_gain | 0.90 |
| 10 | 12:57749135 | T>A, donor_gain | 0.95 |
| 11 | 12:57748615 | TTC>T, acceptor_gain | 0.98 |
| 12 | 12:57748617 | CC>C, acceptor_gain | 0.97 |
| 13 | 12:57748616 | TC>T, acceptor_gain | 0.97 |
| 14 | 12:57748614 | T>C, acceptor_gain | 0.71 |
| 15 | 12:57748613 | ATTTC>A, acceptor_gain | 0.95 |
| 16 | 12:57748618 | C>T, acceptor_gain | 0.82 |
| 17 | 12:57748572 | CTC>C, acceptor_gain | 0.73 |
| 18 | 12:57748571 | GCTC>G, acceptor_gain | 0.84 |
| 19 | 12:57748570 | AGCTC>A, acceptor_gain | 0.79 |
| 20 | 12:57748620 | G>C, acceptor_loss | 0.79 |
| 21 | 12:57748574 | C>T, acceptor_gain | 0.54 |
| 22 | 12:57748569 | GAGCT>G, acceptor_gain | 0.34 |
| 23 | 12:57749164 | C>T, donor_gain | 0.38 |
| 24 | 12:57749165 | ACAG>A, donor_gain | 0.79 |
| 25 | 12:57749166 | CAGC>C, donor_gain | 0.79 |
| 26 | 12:57749172 | T>C, donor_gain | 0.70 |
| 27 | 12:57749122 | T>C, donor_gain | 0.32 |
| 28 | 12:57749167 | A>C, donor_gain | 0.55 |
| 29 | 12:57748592 | T>C, acceptor_gain | 0.50 |
| 30 | 12:57748602 | T>C, acceptor_loss | 0.99 |
Missense Pathogenicity (AlphaMissense)
Total predicted variants: 3,132+ missense variants
Likely pathogenic variants: 180+ (5.7%)
Top 30 Likely-Pathogenic Missense Variants (ranked by am_pathogenicity score):
| Variant | Protein Change | am_pathogenicity | am_class |
|---|---|---|---|
| 1 | 12:57749155 | W238R | 0.999 |
| 2 | 12:57749287 | W238C | 0.998 |
| 3 | 12:57749288 | W238S | 0.996 |
| 4 | 12:57749289 | W238R | 0.999 |
| 5 | 12:57749183 | L272P | 0.990 |
| 6 | 12:57749186 | L272R | 0.984 |
| 7 | 12:57749189 | L271P | 0.992 |
| 8 | 12:57749190 | L271R | 0.974 |
| 9 | 12:57748580 | A286D | 0.997 |
| 10 | 12:57748589 | R283Q | 0.985 |
| 11 | 12:57748590 | R283G | 0.987 |
| 12 | 12:57748603 | F278L | 0.983 |
| 13 | 12:57748604 | F278S | 0.983 |
| 14 | 12:57748605 | F278I | 0.922 |
| 15 | 12:57749270 | L244P | 0.838 |
| 16 | 12:57749270 | L244R | 0.783 |
| 17 | 12:57748610 | L276P | 0.995 |
| 18 | 12:57748610 | L276R | 0.983 |
| 19 | 12:57748612 | M275R | 0.988 |
| 20 | 12:57748613 | M275K | 0.985 |
| 21 | 12:57748603 | F278C | 0.900 |
| 22 | 12:57748598 | P280R | 0.872 |
| 23 | 12:57748598 | P280L | 0.812 |
| 24 | 12:57748303 | P233R | 0.976 |
| 25 | 12:57748303 | P233H | 0.984 |
| 26 | 12:57748303 | P233S | 0.968 |
| 27 | 12:57749285 | P239R | 0.912 |
| 28 | 12:57749285 | P239H | 0.928 |
| 29 | 12:57749309 | G231W | 0.991 |
| 30 | 12:57749309 | G231V | 0.981 |
Pathways & Gene Ontology
Reactome Pathways (19 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-187577 | SCF(Skp2)-mediated degradation of p27/p21 |
| R-HSA-2559580 | Oxidative Stress Induced Senescence |
| R-HSA-2559582 | Senescence-Associated Secretory Phenotype (SASP) |
| R-HSA-2559585 | Oncogene Induced Senescence |
| R-HSA-3214858 | RMTs methylate histone arginines |
| R-HSA-381340 | Transcriptional regulation of white adipocyte differentiation |
| R-HSA-69231 | Cyclin D associated events in G1 |
| R-HSA-75815 | Ubiquitin-dependent degradation of Cyclin D |
| R-HSA-8849470 | PTK6 Regulates Cell Cycle |
| R-HSA-8878166 | Transcriptional regulation by RUNX2 |
| R-HSA-912446 | Meiotic recombination |
| R-HSA-9616222 | Transcriptional regulation of granulopoiesis |
| R-HSA-9630791 | Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 |
| R-HSA-9630794 | Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 |
| R-HSA-9632697 | Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 |
| R-HSA-9632700 | Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 |
| R-HSA-9661069 | Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) |
| R-HSA-9754119 | Drug-mediated inhibition of CDK4/CDK6 activity |
| R-HSA-9929491 | SPOP-mediated proteasomal degradation of PD-L1(CD274) |
MSigDB Gene Sets (524 total)
CDK4 is part of 524 gene sets across MSigDB collections including:
- Reactome pathways: Cell cycle, senescence, transcriptional regulation, mitotic events
- KEGG pathways: Melanoma, glioma, chronic myeloid leukemia, small cell lung cancer, bladder cancer, non-small cell lung cancer, pathways in cancer
- GO/Gene Ontology sets: Cellular processes, molecular functions, cell component ontologies
- Transcription factor targets: ChIP-seq curated sets for multiple TFs
- Gene expression signatures: Disease-specific, tissue-specific, and response-to-treatment signatures
- microRNA targets: Various miRNA prediction datasets
- Immunological signatures: Immune cell markers and states
- Single cell types: Cell-type specific expression patterns
Gene Ontology Annotations (34 total)
Biological Process (16 terms)
| GO ID | Term |
|---|---|
| GO:0000082 | G1/S transition of mitotic cell cycle |
| GO:0007165 | Signal transduction |
| GO:0008284 | Positive regulation of cell population proliferation |
| GO:0009410 | Response to xenobiotic stimulus |
| GO:0010389 | Regulation of G2/M transition of mitotic cell cycle |
| GO:0010468 | Regulation of gene expression |
| GO:0010971 | Positive regulation of G2/M transition of mitotic cell cycle |
| GO:0048146 | Positive regulation of fibroblast proliferation |
| GO:0051301 | Cell division |
| GO:0051726 | Regulation of cell cycle |
| GO:0060260 | Regulation of transcription initiation by RNA polymerase II |
| GO:0061469 | Regulation of type B pancreatic cell proliferation |
| GO:0071222 | Cellular response to lipopolysaccharide |
| GO:0071353 | Cellular response to interleukin-4 |
| GO:1904628 | Cellular response to phorbol 13-acetate 12-myristate |
| GO:1904637 | Cellular response to ionomycin |
Molecular Function (5 terms)
| GO ID | Term |
|---|---|
| GO:0004693 | Cyclin-dependent protein serine/threonine kinase activity |
| GO:0005524 | ATP binding |
| GO:0016538 | Cyclin-dependent protein serine/threonine kinase regulator activity |
| GO:0030332 | Cyclin binding |
| GO:0106310 | Protein serine kinase activity |
Cellular Component (13 terms)
| GO ID | Term |
|---|---|
| GO:0000307 | Cyclin-dependent protein kinase holoenzyme complex |
| GO:0000785 | Chromatin |
| GO:0005634 | Nucleus |
| GO:0005654 | Nucleoplasm |
| GO:0005667 | Transcription regulator complex |
| GO:0005730 | Nucleolus |
| GO:0005737 | Cytoplasm |
| GO:0005829 | Cytosol |
| GO:0005923 | Bicellular tight junction |
| GO:0031965 | Nuclear membrane |
| GO:0097128 | Cyclin D1-CDK4 complex |
| GO:0097129 | Cyclin D2-CDK4 complex |
| GO:0097130 | Cyclin D3-CDK4 complex |
Protein interactions & networks
Protein-Protein Interactions (PPI)
Total Interaction Count (approximate):
- STRING: ~7,256 interactions
- BioGRID: 710 interactions
- IntAct: 438 interactions
TOP 30 Highest-Confidence Interacting Proteins (STRING scores):
| Rank | UniProt ID | Protein Name | STRING Score | Evidence |
|---|---|---|---|---|
| 1 | P24385 | G1/S-specific cyclin-D1 | 999 | Experimental + Database |
| 2 | P42771 | CDK inhibitor 2A (p16-INK4a) | 999 | Experimental + Database |
| 3 | Q96S94 | Cyclin-L2 | 999 | Experimental + Database |
| 4 | P38936 | CDK inhibitor 1 (p21) | 998 | Experimental + Database |
| 5 | P42772 | CDK 4 inhibitor B (p15-INK4b) | 998 | Experimental + Database |
| 6 | P30279 | G1/S-specific cyclin-D2 | 997 | Experimental + Database |
| 7 | P30281 | G1/S-specific cyclin-D3 | 997 | Experimental + Database |
| 8 | P42773 | CDK 4 inhibitor C (p18-INK4c) | 997 | Experimental + Database |
| 9 | P55273 | CDK 4 inhibitor D (p19-INK4d) | 997 | Experimental + Database |
| 10 | P20248 | Cyclin-A2 | 996 | Experimental + Database |
| 11 | P46527 | CDK inhibitor 1B (p27/KIP1) | 996 | Experimental + Database |
| 12 | Q16543 | Hsp90 co-chaperone Cdc37 | 996 | Experimental + Database |
| 13 | P08238 | HSP 90-beta | 992 | Experimental + Database |
| 14 | P07900 | HSP 90-alpha | 990 | Experimental + Database |
| 15 | P06400 | Retinoblastoma-associated protein (Rb) | 985 | Experimental + Database |
| 16 | P24941 | Cyclin-dependent kinase 2 (CDK2) | 983 | Experimental + Database |
| 17 | Q00534 | Cyclin-dependent kinase 6 (CDK6) | 983 | Experimental + Database |
| 18 | P78396 | Cyclin-A1 | 979 | Experimental + Database |
| 19 | O75832 | 26S proteasome subunit 10 (Gankyrin) | 942 | Experimental + Database |
| 20 | O96020 | G1/S-specific cyclin-E2 | 922 | Experimental + Database |
| 21 | P04637 | Cellular tumor antigen p53 | 922 | Experimental + Database |
| 22 | Q01094 | Transcription factor E2F1 | 909 | Experimental + Database |
| 23 | P01106 | Myc proto-oncogene protein | 904 | Experimental + Database |
| 24 | P24864 | G1/S-specific cyclin-E1 | 896 | Experimental + Database |
| 25 | Q00987 | E3 ubiquitin ligase Mdm2 | 884 | Experimental + Database |
| 26 | P14635 | G2/mitotic-specific cyclin-B1 | 865 | Experimental + Database |
| 27 | P31947 | 14-3-3 protein sigma | 846 | Experimental + Database |
| 28 | Q9BT92 | Trichoplein/tumor suppressor | 840 | Experimental + Database |
| 29 | Q99828 | Calcium/integrin-binding protein 1 | 837 | Experimental + Database |
| 30 | P60484 | PTEN phosphatase | 825 | Experimental + Database |
Key BioGRID/IntAct Evidence: Core physical interactions (confidence >0.90) include cyclin D1–D3, CDK inhibitors (p16/p15/p18/p19), and Rb protein. Strong biochemical evidence for interactions with HSP90 chaperones and CDC37 co-chaperone. High-confidence phosphorylation substrate interactions documented via IntAct.
Protein Similarity Networks
Structural/Embedding Similarity (ESM2 - Top 20):
| Rank | UniProt ID | Protein Identity | ESM2 Score | Biological Context |
|---|---|---|---|---|
| 1 | B2MVY4 | CDK-related | 1.0000 | CDK homolog |
| 2 | Q32KY4 | CDK-related | 1.0000 | CDK homolog |
| 3 | P79432 | CDK-related | 0.9998 | CDK4/CDK6-related |
| 4 | Q4KM34 | CDK-related | 0.9998 | CDK homolog |
| 5 | Q9JHU3 | CDK-related | 0.9998 | CDK homolog |
| 6 | P30285 | Cyclin | 0.9997 | Cyclin family |
| 7 | P35426 | Cyclin | 0.9997 | Cyclin family |
| 8 | P11802 | CDK4 | 0.9997 | Self-reference |
| 9 | Q5R7I7 | Kinase | 0.9995 | Serine/threonine kinase |
| 10 | Q8IZL9 | Kinase | 0.9995 | Kinase family |
| 11 | P38973 | CDK-related | 0.9985 | CDK homolog |
| 12 | Q06309 | Kinase | 0.9977 | Serine/threonine kinase |
| 13 | Q38774 | CDK-related | 0.9964 | CDK homolog |
| 14 | Q91727 | CDK-related | 0.9959 | CDK homolog |
| 15 | Q93VK0 | Kinase | 0.9939 | Kinase family |
| 16 | Q8SQU8 | CDK-related | 0.9877 | CDK homolog |
| 17 | P54665 | Cyclin | 0.9887 | Cyclin family |
| 18 | P54666 | Cyclin | 0.9904 | Cyclin family |
| 19 | Q00534 | CDK6 | 0.9993 | CDK family member |
| 20 | Q64261 | Kinase | 0.9993 | Serine/threonine kinase |
Sequence Homology (DIAMOND - Top 20):
| Rank | UniProt ID | Protein Identity | Identity (%) | Bitscore | Alignment Hits |
|---|---|---|---|---|---|
| 1 | B2MVY4 | CDK-related | 100.00 | 615 | 100 |
| 2 | Q32KY4 | CDK-related | 100.00 | 615 | 100 |
| 3 | C6KTB8 | CDK-related | 94.40 | 1701 | 41 |
| 4 | O43948 | CDK-related | 94.40 | 1700 | 92 |
| 5 | B8Y466 | CDK-related | 94.70 | 1014 | 100 |
| 6 | Q5RD27 | Kinase | 99.40 | 1242 | 100 |
| 7 | Q96SB4 | Kinase | 99.40 | 1242 | 100 |
| 8 | P30285 | Cyclin | 98.70 | 603 | 100 |
| 9 | P35426 | Cyclin | 98.70 | 605 | 100 |
| 10 | P79432 | CDK4-related | 99.00 | 611 | 100 |
| 11 | Q00534 | CDK6 | 96.30 | 634 | 100 |
| 12 | Q64261 | Kinase | 96.30 | 632 | 100 |
| 13 | P17613 | CDK-related | 95.50 | 625 | 100 |
| 14 | P24381 | CDK-related | 95.50 | 627 | 100 |
| 15 | O54781 | CDK-related | 91.60 | 1132 | 100 |
| 16 | O70551 | CDK-related | 91.60 | 1139 | 100 |
| 17 | P78362 | CDK-related | 91.90 | 1123 | 100 |
| 18 | Q9Z0G2 | Kinase | 93.20 | 993 | 100 |
| 19 | Q9UPE1 | CDK-related | 94.70 | 1009 | 100 |
| 20 | P04413 | CDK-related | 73.80 | 705 | 100 |
Network Summary: CDK4 occupies a central hub in cell cycle regulation networks, interacting primarily with:
- Cyclin partners (D-type, A, E cyclins) for G1/S checkpoint control
- Endogenous inhibitors (p16, p15, p18, p19) for negative feedback regulation
- Rb pathway (Rb, E2F factors) for G1/S restriction checkpoint
- Chaperone machinery (HSP90, Cdc37) for protein stability
- Ubiquitin regulation (proteasome, Mdm2, PTEN) for cell cycle transitions
- Tumor suppressors (p53, Rb) for checkpoint control and apoptosis signaling
Transcription factor regulatory data
CDK4 is not a transcription factor. CDK4 (Cyclin-dependent kinase 4) is a serine/threonine protein kinase involved in cell cycle regulation, not a transcription factor. Therefore, downstream targets and DNA binding motif sections do not apply.
Upstream regulators (45 transcription factors that regulate CDK4):
Activation (12):
- E2F1 (predicted via GEREDB)
- HDAC1 (predicted)
- MYC (High confidence, predicted)
- NFKB (High confidence, predicted)
- NFKB1 (Low confidence, predicted)
- PDGFB (predicted)
- POU4F2 (High confidence, predicted)
- SATB1 (predicted)
- SOX9 (predicted)
- SP1 (High confidence, predicted)
- STAT3 (predicted)
- ZEB1 (predicted)
Repression (8):
- CEBPA (predicted)
- IRF1 (predicted)
- LRRC4 (predicted)
- NFATC2 (High confidence, predicted)
- NR3C1 (predicted)
- PPARG (predicted)
- SOX6 (predicted)
- TGFB1 (predicted)
Unknown regulation type (5):
- ATF2 (High confidence, predicted)
- ESR1 (predicted)
- ETS1 (predicted)
- JUND (High confidence, predicted)
- TP53 (High confidence, predicted)
- USF1 (High confidence, predicted)
Unspecified regulation (20):
- EZH2, FOS, GATA4, HR, IRF3, JARID2, KLF4, KSR1, MAFA, NEUROG3, NFKBID, PAX3, PARP1, RUNX1, SIN3B, TFDP1, USF2, YBX3
All evidence types are predicted (from computational databases like GEREDB); no ChIP-seq or experimentally validated interactions are annotated in the current collectri dataset for these CDK4 regulations.
Drug & pharmacology data
CDK4 is a well-established drug target. CDK4 is a cyclin-dependent kinase central to cell cycle progression (G1/S phase), primarily targeted in cancer therapeutics.
Targeting molecules: ChEMBL inventory
- Total: 1,422 molecules in ChEMBL targeting CDK4 (CHEMBL331)
TOP 30 approved drugs (Phase 4) & development candidates by highest phase
| Rank | Molecule ID | Name | Type | Highest Phase | Clinical Trials |
|---|---|---|---|---|---|
| 1 | CHEMBL189963 | PALBOCICLIB (Ibrance) | CDK4/6 inhibitor | Phase 4 | 304 |
| 2 | CHEMBL3301610 | ABEMACICLIB (Verzenio) | CDK4/6 inhibitor | Phase 4 | 208 |
| 3 | CHEMBL3545110 | RIBOCICLIB (Kisqali) | CDK4/6 inhibitor | Phase 4 | 161 |
| 4 | CHEMBL2028663 | DABRAFENIB (Tafinlar) | BRAF/CDK4 inhibitor | Phase 4 | 137 |
| 5 | CHEMBL3301612 | ENCORAFENIB (Braftovi) | BRAF/CDK4 inhibitor | Phase 4 | 83 |
| 6 | CHEMBL3301622 | GILTERITINIB (Xospata) | FLT3/CDK4 inhibitor | Phase 4 | 59 |
| 7 | CHEMBL2403108 | CERITINIB (Zykadia) | ALK/CDK4 inhibitor | Phase 4 | 45 |
| 8 | CHEMBL1287853 | FEDRATINIB (Inrebic) | JAK2/CDK4 inhibitor | Phase 4 | 27 |
| 9 | CHEMBL2103840 | DINACICLIB (SCH-727965) | CDK inhibitor | Phase 3 | 18 |
| 10 | CHEMBL14762 | SELICICLIB (CYC-202) | CDK inhibitor | Phase 2 | 6 |
Mechanism notes: Most approved drugs are dual CDK4/6 inhibitors used in HR+/HER2- breast cancer (palbociclib, abemaciclib, ribociclib) as first/second-line endocrine therapy combinations. Others are multi-kinase inhibitors with CDK4 off-target activity (BRAF/JAK2/ALK/FLT3 inhibitors).
TOP 20 clinical trials involving CDK4-targeting drugs
Sample of pivotal trials (palbociclib examples):
- NCT01740427 — PALOMA-2: Palbociclib + Letrozole vs Letrozole | Phase 3 | COMPLETED
- NCT01942135 — PALOMA-3: Palbociclib + Fulvestrant | Phase 3 | COMPLETED
- NCT02028507 — Palbociclib + Endocrine vs Capecitabine | Phase 3 | COMPLETED
- NCT02297438 — PALOMA-4: Asian postmenopausal cohort | Phase 3 | COMPLETED
- NCT03423199 — Palbociclib + Tamoxifen (Asian) | Phase 3 | ACTIVE
- NCT04191499 — Inavolisib + Palbociclib + Fulvestrant | Phase 2/3 | ACTIVE
- NCT04546009 — Giredestrant + Palbociclib vs Letrozole + Palbociclib | Phase 3 | ACTIVE
- NCT04966481 — Palbociclib + Cetuximab for CDKN2A-altered HNSCC | Phase 3 | RECRUITING
- NCT05501886 — Gedatolisib + Fulvestrant ± Palbociclib | Phase 3 | ACTIVE
- NCT05909397 — Vepdegestrant + Palbociclib vs Letrozole + Palbociclib | Phase 3 | ACTIVE
(Additional trials cover abemaciclib MONARCH studies, ribociclib MONALEESA studies, and biomarker-driven CDK4/6 inhibitor combinations across 100+ active/completed trials)
Pharmacogenomics & dosing guidelines
Biomarkers driving CDK4-targeted therapy:
- CDK4 amplification: Predictive biomarker for sensitivity to CDK4/6 inhibitors; used in basket trials (e.g., NCT03310879 — Abemaciclib in tumors with CDK4 amplification)
- CDKN2A homozygous deletion: Associated with improved response to abemaciclib in HNSCC
- RB pathway alterations: Selection criterion for CDK4/6 inhibitor trials
Known drug-gene interactions & dosing:
- No specific CDK4 polymorphism-based dosing guidelines are established at population level
- CDK4/6 inhibitors have standard dosing (palbociclib 125 mg daily 3-weeks-on/1-week-off; abemaciclib 150–200 mg BID; ribociclib 600 mg daily); dose adjustments driven by toxicity, not CDK4 variants
- ER/PR & HER2 status (not CDK4 variants) determine indication and combination partner selection
- CDK4 is flagged as VIP (Very Important Pharmacogene) in PharmGKB with variant annotations, though clinical utility in germline pharmacogenomics is currently limited; somatic CDK4 amplification is the therapeutically actionable alteration
Current status: CDK4 is a primary oncology target but lacks established pharmacogenomic guidelines for personalizing dosing based on germline variants; therapy selection is driven by tumor molecular profile (CDK4 copy number, RB pathway status, ER/PR/HER2 status) rather than patient germline pharmacogenetics.
Expression profiles
Based on Bgee, SCXA, and available biobtree data for CDK4:
Tissue Expression (Bgee)
CDK4 shows ubiquitous expression across 138 tissues/conditions with high quality data. Expression breadth indicates it’s widely expressed across the body.
Top 30 Tissues/Anatomical Structures (expression score | quality):
| Rank | Tissue/Structure | Score | Quality |
|---|---|---|---|
| 1-2 | Ganglionic eminence, Embryo | 98.33 | Gold |
| 3 | Ventricular zone | 98.30 | Gold |
| 4 | Stromal cell of endometrium | 97.91 | Gold |
| 5 | Right adrenal gland | 97.21 | Gold |
| 6-7 | Right/Ovary | 97.13 | Gold |
| 8 | Smooth muscle tissue | 97.11 | Gold |
| 9 | Right adrenal gland cortex | 97.06 | Gold |
| 10 | Left ovary | 97.05 | Gold |
| 11 | Left adrenal gland | 96.92 | Gold |
| 12 | Left adrenal gland cortex | 96.76 | Gold |
| 13 | Left uterine tube | 96.75 | Gold |
| 14-16 | Ectocervix, Adrenal gland, Endocervix | 96.70 | Gold |
| 17 | Body of uterus | 96.66 | Gold |
| 18 | Myometrium | 96.43 | Gold |
| 19 | Adenohypophysis | 96.38 | Gold |
| 20 | Fallopian tube | 96.35 | Gold |
| 21 | Pancreas | 96.34 | Gold |
| 22-23 | Gall bladder, Islet of Langerhans | 96.31 | Gold |
| 24 | Body of pancreas | 96.29 | Gold |
| 25 | Pituitary gland | 96.16 | Gold |
| 26 | Vermiform appendix | 96.06 | Gold |
| 27 | Adrenal tissue | 96.03 | Gold |
| 28 | Right coronary artery | 95.95 | Gold |
| 29 | Lymph node | 95.92 | Gold |
| 30 | Uterine cervix | 95.91 | Gold |
Pattern: CDK4 is highly expressed in reproductive tissues (ovaries, uterus, cervix, fallopian tubes), endocrine tissues (adrenal glands, pancreatic islets, pituitary), and embryonic structures. Average expression score: 93.45 across all tissues.
Single-Cell Expression (SCXA - Single Cell Expression Atlas)
CDK4 is a marker gene in 11 experiments across 452 cell clusters.
- Max mean expression: 2197.80 (transcripts per million equivalent)
- Average mean expression: 110.65
Key Single-Cell Datasets:
| Dataset ID | Description | Cell Count | Species |
|---|---|---|---|
| E-HCAD-4 | Census of Immune Cells | 791,344 | Human |
| E-HCAD-56 | Developing spinal cord atlas | 245,394 | Human |
| E-HCAD-5 | Organoid inter-individual variation | 25,049 | Human |
| E-MTAB-8884 | CMML stem cells | 9,386 | Human |
| E-HCAD-13 | Induced dendritic cells | 8,012 | Human |
| E-GEOD-89232 | Conventional dendritic cells | 957 | Human |
| E-MTAB-6379 | T lymphocytes (H7N9 infected) | 119 | Human |
| E-MTAB-2983 | Ovarian stem cells | 38 | Human |
Notable Cell Type Patterns (from SCXA):
- Strong presence in immune cell populations (lymphocytes, dendritic cells)
- High expression in developmental tissues (spinal cord, organoid models)
- Present as marker across 452 distinct cell clusters, indicating cell type diversity
Limitation: Detailed per-cell-type rankings for Tabula Sapiens and HCA-integrated datasets are not available in current biobtree queries. SCXA integrates multiple single-cell datasets and shows CDK4 as a consistent marker, suggesting it marks diverse cell types across tissues.
Disease associations
Mendelian / Monogenic Diseases
| Disease | Disease ID | Inheritance | Evidence Level |
|---|---|---|---|
| Melanoma, cutaneous malignant, susceptibility to, 3 | OMIM:609048 / MONDO:0012183 / Orphanet:618 | Autosomal dominant | Definitive (G2P), Strong (Ambry/Labcorp) |
| Familial melanoma | MONDO:0018961 / Orphanet:618 | Autosomal dominant | Curated |
| Malignant pancreatic neoplasm | MONDO:0009831 | Autosomal dominant | Moderate (Genomics England PanelApp) |
| Hereditary neoplastic syndrome | MONDO:0015356 | Autosomal dominant | Curated |
| Gastric cancer | MONDO:0001056 | Autosomal dominant | Associated via ClinVar |
| Ovarian cancer | MONDO:0008170 / Orphanet:213500 | Autosomal dominant | Associated via ClinVar |
| Diffuse pediatric-type high-grade glioma (H3-wildtype, IDH-wildtype) | MONDO:0858939 | Autosomal dominant | Associated via ClinVar |
Phenotype Associations (HPO Terms)
19 phenotype terms associated with CDK4:
| HPO ID | Phenotype |
|---|---|
| HP:0002861 | Melanoma |
| HP:0012056 | Cutaneous melanoma |
| HP:0001054 | Numerous nevi |
| HP:0001062 | Atypical nevus |
| HP:0001074 | Atypical nevi in non-sun exposed areas |
| HP:0001480 | Freckling |
| HP:0003764 | Nevus |
| HP:0002894 | Neoplasm of the pancreas |
| HP:0006753 | Neoplasm of the stomach |
| HP:0100013 | Neoplasm of the breast |
| HP:0000006 | Autosomal dominant inheritance |
| HP:0001482 | Subcutaneous nodule |
| HP:0000488 | Retinopathy |
| HP:0000958 | Dry skin |
| HP:0001595 | Abnormal hair morphology |
| HP:0002071 | Abnormality of extrapyramidal motor function |
| HP:0002579 | Gastrointestinal dysmotility |
| HP:0012211 | Abnormal renal physiology |
| HP:0100763 | Abnormality of the lymphatic system |
Complex Disease / GWAS Associations
6 GWAS associations found:
| Trait | Chromosome | P-value | Associated Gene(s) |
|---|---|---|---|
| Brain morphology (MOSTest) | 12 | 2.0 × 10⁻¹¹ | MBD6 |
| Rheumatoid arthritis | 12 | 1.0 × 10⁻⁷ | OS9, OS9-AS1 |
| Rheumatoid arthritis | 12 | 9.0 × 10⁻⁸ | OS9, OS9-AS1 |
| Rheumatoid arthritis | 12 | 7.0 × 10⁻⁸ | OS9, OS9-AS1 |
| Rheumatoid arthritis | 12 | 1.0 × 10⁻⁷ | OS9, OS9-AS1 |
| Celiac disease or Rheumatoid arthritis | 12 | 4.0 × 10⁻⁶ | B4GALNT1, RPL13AP23 |
Summary: CDK4 is primarily known for germline mutations causing melanoma predisposition (autosomal dominant), with additional cancer susceptibility associations including pancreatic, gastric, ovarian, and breast cancers. GWAS signals primarily implicate nearby genes rather than CDK4 directly, with strongest associations to rheumatoid arthritis and brain morphology variants.