CDK4 Gene (Protein Coding)

Cyclin Dependent Kinase 4

GC12M057743
GIFtS:
56
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 regu... See more...

Aliases for CDK4 Gene

Aliases for CDK4 Gene

  • Cyclin Dependent Kinase 4 2 3 5
  • Cell Division Protein Kinase 4 3 4
  • Cyclin-Dependent Kinase 4 3 4
  • EC 2.7.11.22 4 54
  • PSK-J3 3 4
  • EC 2.7.11 54
  • CMM3 3

External Ids for CDK4 Gene

Previous GeneCards Identifiers for CDK4 Gene

  • GC12M058284
  • GC12M057858
  • GC12M056428
  • GC12M058142
  • GC12M055178

Summaries for CDK4 Gene

Entrez Gene Summary for CDK4 Gene

  • 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. [provided by RefSeq, Jul 2008]

CIViC Summary for CDK4 Gene

  • CDK4, along with its partner CDK6, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors.

GeneCards Summary for CDK4 Gene

CDK4 (Cyclin Dependent Kinase 4) is a Protein Coding gene. Diseases associated with CDK4 include Melanoma, Cutaneous Malignant 3 and Myeloma, Multiple. Among its related pathways are Cellular Senescence (REACTOME) and Meiosis. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is CDK6.

UniProtKB/Swiss-Prot Summary for CDK4 Gene

  • 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.

Tocris Summary for CDK4 Gene

  • Cdks (cyclin-dependent kinases) are heteromeric serine/threonine kinases that control progression through the cell cycle in concert with their regulatory subunits, the cyclins. Although there are 12 different cdk genes, only 5 have been shown to directly drive the cell cycle.

Gene Wiki entry for CDK4 Gene

Additional gene information for CDK4 Gene

No data available for PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for CDK4 Gene

Genomics for CDK4 Gene

GeneHancer (GH) Regulatory Elements for CDK4 Gene

Promoters and enhancers for CDK4 Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around CDK4 on UCSC Golden Path with GeneCards custom track

Top Transcription factor binding sites by QIAGEN in the CDK4 gene promoter:
  • ATF-2
  • c-Jun
  • C/EBPalpha
  • CREB
  • deltaCREB

Genomic Locations for CDK4 Gene

Genomic Locations for CDK4 Gene
chr12:57,747,727-57,756,013
(GRCh38/hg38)
Size:
8,287 bases
Orientation:
Minus strand
chr12:58,141,510-58,149,796
(GRCh37/hg19)
Size:
8,287 bases
Orientation:
Minus strand

Genomic View for CDK4 Gene

Genes around CDK4 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
CDK4 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for CDK4 Gene
GeneLoc Logo Genomic Neighborhood • Exon Structure • Gene Density

RefSeq DNA sequence for CDK4 Gene

Proteins for CDK4 Gene

Products:

  1. Antibody
  2. Protein
  3. Assay

  • Protein details for CDK4 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    P11802-CDK4_HUMAN
    Recommended name:
    Cyclin-dependent kinase 4
    Protein Accession:
    P11802
    Secondary Accessions:
    • B2R9A0
    • B4DNF9
    • O00576
    • Q6FG61

    Protein attributes for CDK4 Gene

    Size:
    303 amino acids
    Molecular mass:
    33730 Da
    Quaternary 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 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).

    Three dimensional structures from OCA and Proteopedia for CDK4 Gene

    Alternative splice isoforms for CDK4 Gene

    UniProtKB/Swiss-Prot:

neXtProt entry for CDK4 Gene

Protein Expression for CDK4 Gene

See protein expression from ProteomicsDB, MOPED, PaxDb, and MaxQB

Selected DME Specific Peptides for CDK4 Gene

P11802:
  • GCIFAEM
  • RKPLFCGNSEADQL
  • WSVGCIFAE
  • ETIKDLM
  • YEPVAEIGVGAYGTVYKARD
  • QMALTPVVVTLWYRAPEVLLQSTYATPVD
  • TLVFEHVDQDL
  • VKLADFG
  • HPNVVRL
  • VVTLWYR
  • ENILVTS
  • WSVGCIFAEMFRRKPLF
  • LADFGLA
  • RDLKPEN
  • KRISAFRALQHSYLHK
  • VHRDLKP
  • IVHRDLK

Post-translational modifications for CDK4 Gene

  • 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.
  • Ubiquitination at Lys22, Lys155, Lys35, Lys211, Lys106, Lys282, and Lys297
  • Modification sites at PhosphoSitePlus

Other Protein References for CDK4 Gene

ENSEMBL proteins:
REFSEQ proteins:

Antibody Products

  • Abcam antibodies for CDK4

Domains & Families for CDK4 Gene

Gene Families for CDK4 Gene

HGNC:
IUPHAR :
Human Protein Atlas (HPA):
  • Cancer-related genes
  • Disease related genes
  • Enzymes
  • FDA approved drug targets
  • Plasma proteins
  • Predicted intracellular proteins

Protein Domains for CDK4 Gene

InterPro:
ProtoNet:

Suggested Antigen Peptide Sequences for CDK4 Gene

GenScript: Design optimal peptide antigens:
  • cDNA FLJ60730, highly similar to Cell division protein kinase 4 (EC 2.7.11.22) (B4DNF9_HUMAN)
  • PSK-J3 (CDK4_HUMAN)
  • Cyclin-dependent kinase 4, isoform CRA_b (Q6LC83_HUMAN)

Graphical View of Domain Structure for InterPro Entry

P11802

UniProtKB/Swiss-Prot:

CDK4_HUMAN :
  • Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.
Family:
  • Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.
genes like me logo Genes that share domains with CDK4: view

Function for CDK4 Gene

Products:

  1. Animal Model
  2. CRISPR
  3. miRNA
  4. Inhibitory RNA
  5. Clone
  6. Cell Line

Molecular function for CDK4 Gene

UniProtKB/Swiss-Prot 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.
UniProtKB/Swiss-Prot CatalyticActivity:
Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22; Evidence={ECO:0000269 PubMed:19075005, ECO:0000269 PubMed:19237565, ECO:0000269 PubMed:9106657};.
UniProtKB/Swiss-Prot CatalyticActivity:
Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.22; Evidence={ECO:0000269 PubMed:19075005, ECO:0000269 PubMed:19237565, ECO:0000269 PubMed:9106657};.
UniProtKB/Swiss-Prot EnzymeRegulation:
Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequent activation.
GENATLAS Biochemistry:
cyclin dependent kinase 4 involved in cell cycle regulation (G1 to S transition),complexing with cyclin D (D1,D2,D3),amplified in malignant glioblastoma and anaplastic astrocytoma,and in diffuse large B cell lymphoma ; amplified in osteosarcoma with OS9,SAS and PRIM1and in sporadic breast carcinomas,predisposing to familial melanoma by inducing abnormal repair of ultraviolet radiation. Loss of CDK4 expression causes insulin deficient diabetes,and CDK4 activation results in B islet cell hyperplasia in mice

Enzyme Numbers (IUBMB) for CDK4 Gene

Phenotypes From GWAS Catalog for CDK4 Gene

Gene Ontology (GO) - Molecular Function for CDK4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000166 nucleotide binding IEA --
GO:0004672 protein kinase activity IEA --
GO:0004674 protein serine/threonine kinase activity IEA --
GO:0004693 cyclin-dependent protein serine/threonine kinase activity IDA,TAS --
GO:0005515 protein binding IPI 7568034
genes like me logo Genes that share ontologies with CDK4: view
genes like me logo Genes that share phenotypes with CDK4: view

Human Phenotype Ontology for CDK4 Gene

HPO Id HPO Name Alternative Ids Definition Synonyms

Animal Models for CDK4 Gene

MGI Knock Outs for CDK4:
  • Cdk4 Cdk4<tm1Bbd>
  • Cdk4 Cdk4<tm1Kiyo>
  • Cdk4 Cdk4<tm2.1Bbd>
  • Cdk4 Cdk4<tm1b(NCOM)Mfgc>

Animal Model Products

CRISPR Products

miRNA for CDK4 Gene

miRTarBase miRNAs that target CDK4

Clone Products

  • Addgene plasmids for CDK4

No data available for Transcription Factor Targets and HOMER Transcription for CDK4 Gene

Localization for CDK4 Gene

Subcellular locations from UniProtKB/Swiss-Prot for CDK4 Gene

Cytoplasm. Nucleus. Membrane. Note=Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress through G(1) phase. The complex accumulates on the nuclear membrane and enters the nucleus on transition from G(1) to S phase. Also present in nucleoli and heterochromatin lumps. Colocalizes with RB1 after release into the nucleus.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for CDK4 gene
Compartment Confidence
nucleus 5
cytosol 5
extracellular 2
cytoskeleton 2
mitochondrion 2
plasma membrane 1
peroxisome 1
endoplasmic reticulum 1

Subcellular locations from the

Human Protein Atlas (HPA)
  • Cytosol (3)
  • Nuclear membrane (3)
  • Nucleoli (3)
  • Nucleus (3)
See all subcellular structures

Gene Ontology (GO) - Cellular Components for CDK4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000307 cyclin-dependent protein kinase holoenzyme complex IDA 17420273
GO:0000785 chromatin IDA 18827403
GO:0005634 nucleus IBA,IDA 16109376
GO:0005654 nucleoplasm TAS --
GO:0005667 transcription factor complex IEA --
genes like me logo Genes that share ontologies with CDK4: view

Pathways & Interactions for CDK4 Gene

genes like me logo Genes that share pathways with CDK4: view

Pathways by source for CDK4 Gene

1 Sino Biological pathway for CDK4 Gene
12 Qiagen pathways for CDK4 Gene
  • Calpain Protease Regulates Cellular Mechanics
  • Cell Cycle Control by BTG Proteins
  • Cell Cycle Control of Chromosomal Replication
  • Cyclins and Cell Cycle Regulation
  • Epithelial Tight Junctions
1 Cell Signaling Technology pathway for CDK4 Gene
1 GeneTex pathway for CDK4 Gene

SIGNOR curated interactions for CDK4 Gene

Activates:
Inactivates:
Is activated by:
Is inactivated by:
Other effect:

Gene Ontology (GO) - Biological Process for CDK4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000079 regulation of cyclin-dependent protein serine/threonine kinase activity IEA --
GO:0000082 G1/S transition of mitotic cell cycle IMP 7603984
GO:0002088 lens development in camera-type eye IEA --
GO:0006367 transcription initiation from RNA polymerase II promoter TAS --
GO:0006468 protein phosphorylation IEA,IDA 8114739
genes like me logo Genes that share ontologies with CDK4: view

Drugs & Compounds for CDK4 Gene

Products:

  1. Drug

(168) Drugs for CDK4 Gene - From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, HMDB, Tocris, and Novoseek

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
Palbociclib Approved, Investigational Pharma Target, inhibitor, Inhibition 204
Doxorubicin Approved, Investigational Pharma Topo II inhibitor,immunosuppresive antineoplastic antibiotic 2016
Paclitaxel Approved, Vet_approved Pharma Tubulin and Bcl2 inhibitor, Taxanes 3454
abemaciclib Approved, Investigational Pharma Target, inhibitor 0
fostamatinib Approved, Investigational Pharma Target, inhibitor Kinase Inhibitors 0

(45) Additional Compounds for CDK4 Gene - From: HMDB, Novoseek, and Tocris

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
ADP
  • 5'-Adenylphosphoric acid
  • Adenosine 5'-diphosphate
  • ADENOSINE-5'-diphosphATE
  • H3ADP
  • 5'-Adenylphosphate
 Full agonist, Agonist, Partial agonist, Antagonist, Gating inhibitor 58-64-0
(R)-CR8
294646-77-8
Arcyriaflavin A
118458-54-1

(5) Tocris Compounds for CDK4 Gene

Compound Action Cas Number
(R)-CR8 Dual cdk1/cdk5 inhibitor; also inhibits CK1 294646-77-8
Arcyriaflavin A Potent cdk4/cyclin D1 and CaM Kinase II inhibitor. Antiviral agent (anti-HCMV) 118458-54-1
AZD 5438 Potent cyclin-dependent kinase (cdk) 1, 2 and 9 inhibitor 602306-29-6
Olomoucine Cyclin-dependent kinase inhibitor 101622-51-9
SU 9516 Potent cdk2 inhibitor 377090-84-1

(22) ApexBio Compounds for CDK4 Gene

Compound Action Cas Number
[Ala92]-p16 (84-103) 189064-08-2
AMG 925 FLT3/CDK4 inhibitor,potent and selective 1401033-86-0
AT7519 Multi-CDK inhibitor 844442-38-2
BS-181 HCl CDK7 inhibitor,highly selective 1397219-81-6
CDK4 inhibitor CDK4/Cyclin D1 inhibitor 1256963-02-6
Flavopiridol hydrochloride 131740-09-5
LDC000067 1073485-20-7
LEE011 CDK4/6 inhibitor 1211441-98-3
LEE011 hydrochloride CDK inhibitor 1211443-80-9
LEE011 succinate CDK inhibitor 1374639-75-4
LEE011 succinate hydrate CDK inhibitor 1374639-79-8
LY2835219 CDK4/6 inhibitor,potent and selective 1231930-82-7
LY2835219 free base CDK inhibitor 1231929-97-7
NSC 625987 141992-47-4
P276-00 CDK-1/CDK4/CDK9 inhibitor 920113-03-7
Palbociclib (PD0332991) Isethionate CDK4/6 inhibitor,highly selective 827022-33-3
PD 0332991 (Palbociclib) HCl CDK4/6 inhibitor,highly selective 827022-32-2
PHA-848125 CDK inhibitor,potent and ATP-competitive 802539-81-7
Purvalanol A 212844-53-6
Purvalanol B CDK1/CDK2/CDK4 inhibitor 212844-54-7
R547 CDK1/2/4 inhibitor,ATP-competitive 741713-40-6
Ryuvidine 265312-55-8
genes like me logo Genes that share compounds with CDK4: view

Transcripts for CDK4 Gene

Products:

  1. CRISPR
  2. miRNA
  3. Inhibitory RNA
  4. Clone

mRNA/cDNA for CDK4 Gene

(2) REFSEQ mRNAs :
(14) Additional mRNA sequences :
(974) Selected AceView cDNA sequences:
(15) Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

CRISPR Products

Clone Products

  • Addgene plasmids for CDK4

Alternative Splicing Database (ASD) splice patterns (SP) for CDK4 Gene

ExUns: 1a · 1b · 1c · 1d · 1e ^ 2a · 2b · 2c · 2d ^ 3 ^ 4a · 4b ^ 5 ^ 6 ^ 7a · 7b ^ 8a · 8b ^ 9a · 9b
SP1: - - -
SP2: - - -
SP3: - - - - -
SP4: - - - - - -
SP5: - -
SP6: - - - - - - - - - -
SP7:
SP8: - -
SP9:

Relevant External Links for CDK4 Gene

GeneLoc Exon Structure for
CDK4
ECgene alternative splicing isoforms for
CDK4

Expression for CDK4 Gene

Products:

  1. Primer
  2. Gene Expression Assay

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and CGAP SAGE for CDK4 Gene

mRNA expression in normal human tissues for CDK4 Gene
mRNA expression by BioGPS for CDK4 GenemRNA expression by GTEx for CDK4 Gene

Protein differential expression in normal tissues from HIPED for CDK4 Gene

This gene is overexpressed in Uterus (15.2).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for CDK4 Gene



Protein tissue co-expression partners for CDK4 Gene

- Elite partner

NURSA nuclear receptor signaling pathways regulating expression of CDK4 Gene:

CDK4

SOURCE GeneReport for Unigene cluster for CDK4 Gene:

Hs.95577

Evidence on tissue expression from TISSUES for CDK4 Gene

  • Muscle(5)
  • Nervous system(4.6)
  • Skin(4.3)
  • Lung(4)
  • Intestine(3.8)
  • Liver(3.2)
  • Kidney(3.1)
  • Pancreas(3)
  • Blood(2.9)
  • Bone marrow(2.6)
  • Eye(2.6)
  • Heart(2.5)
  • Lymph node(2.5)
  • Stomach(2.4)
  • Thyroid gland(2.4)
  • Adrenal gland(2.2)

Phenotype-based relationships between genes and organs from Gene ORGANizer for CDK4 Gene

Germ Layers:
  • ectoderm
  • mesoderm
Systems:
  • integumentary
  • lymphatic
  • nervous
Regions:
Head and neck:
  • brain
  • eye
  • head
General:
  • skin
genes like me logo Genes that share expression patterns with CDK4: view