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Protein

Cyclin-dependent kinase 4

Gene

CDK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.3 Publications

Enzyme regulationi

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.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei35ATPPROSITE-ProRule annotation1
Active sitei140Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi12 – 20ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cyclin binding Source: UniProtKB
  • cyclin-dependent protein serine/threonine kinase activity Source: BHF-UCL
  • cyclin-dependent protein serine/threonine kinase regulator activity Source: Reactome

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processCell cycle, Cell division
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22 2681
ReactomeiR-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-69229 Ubiquitin-dependent degradation of Cyclin D1
R-HSA-69231 Cyclin D associated events in G1
R-HSA-8849470 PTK6 Regulates Cell Cycle
R-HSA-8878166 Transcriptional regulation by RUNX2
R-HSA-912446 Meiotic recombination
SignaLinkiP11802
SIGNORiP11802

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 4 (EC:2.7.11.22)
Alternative name(s):
Cell division protein kinase 4
PSK-J3
Gene namesi
Name:CDK4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000135446.16
HGNCiHGNC:1773 CDK4
MIMi123829 gene
neXtProtiNX_P11802

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Melanoma, cutaneous malignant 3 (CMM3)4 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:609048
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00620024R → C in CMM3; somatic and familial; generates a dominant oncogene resistant to inhibition by p16(INK4a). 2 PublicationsCorresponds to variant dbSNP:rs11547328Ensembl.1
Natural variantiVAR_00620124R → H in CMM3. 1 PublicationCorresponds to variant dbSNP:rs104894340Ensembl.1
Natural variantiVAR_02115241N → S in CMM3; sporadic. 1 PublicationCorresponds to variant dbSNP:rs144890720Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi172T → A: Weak enzyme activity towards RB1, but no effect on binding of CCDN1 nor CCDN3. 1 Publication1
Mutagenesisi172T → E: Retains moderate enzyme activity. 1 Publication1
Mutagenesisi173P → S: No effect on in vitro phosphorylation by CDK7. Greatly reduced T-172 phosphorylation and enzyme activity. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi1019
MalaCardsiCDK4
MIMi609048 phenotype
OpenTargetsiENSG00000135446
Orphaneti99970 Dedifferentiated liposarcoma
618 Familial melanoma
99971 Well-differentiated liposarcoma
PharmGKBiPA102

Chemistry databases

ChEMBLiCHEMBL331
DrugBankiDB03496 Flavopiridol
DB09073 Palbociclib
DB02733 Purvalanol
DB11730 Ribociclib
GuidetoPHARMACOLOGYi1976

Polymorphism and mutation databases

BioMutaiCDK4
DMDMi1168867

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000857782 – 303Cyclin-dependent kinase 4Add BLAST302

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei172PhosphothreonineCombined sources4 Publications1

Post-translational modificationi

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.5 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP11802
MaxQBiP11802
PaxDbiP11802
PeptideAtlasiP11802
PRIDEiP11802

PTM databases

iPTMnetiP11802
PhosphoSitePlusiP11802

Expressioni

Gene expression databases

BgeeiENSG00000135446
CleanExiHS_CDK4
ExpressionAtlasiP11802 baseline and differential
GenevisibleiP11802 HS

Organism-specific databases

HPAiCAB069405
HPA006024

Interactioni

Subunit structurei

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).By similarity12 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cyclin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi107454, 165 interactors
CORUMiP11802
DIPiDIP-875N
ELMiP11802
IntActiP11802, 111 interactors
MINTiP11802
STRINGi9606.ENSP00000257904

Chemistry databases

BindingDBiP11802

Structurei

Secondary structure

1303
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi7 – 13Combined sources7
Beta strandi15 – 17Combined sources3
Beta strandi20 – 24Combined sources5
Turni26 – 28Combined sources3
Beta strandi31 – 40Combined sources10
Helixi51 – 63Combined sources13
Helixi64 – 66Combined sources3
Beta strandi74 – 82Combined sources9
Beta strandi84 – 94Combined sources11
Beta strandi97 – 99Combined sources3
Helixi100 – 105Combined sources6
Turni109 – 111Combined sources3
Helixi114 – 133Combined sources20
Turni143 – 145Combined sources3
Beta strandi146 – 148Combined sources3
Turni150 – 152Combined sources3
Beta strandi154 – 156Combined sources3
Helixi162 – 169Combined sources8
Helixi172 – 175Combined sources4
Turni183 – 185Combined sources3
Beta strandi186 – 189Combined sources4
Helixi195 – 208Combined sources14
Beta strandi209 – 211Combined sources3
Helixi219 – 230Combined sources12
Turni235 – 237Combined sources3
Beta strandi242 – 244Combined sources3
Helixi246 – 248Combined sources3
Helixi257 – 260Combined sources4
Helixi266 – 275Combined sources10
Helixi280 – 282Combined sources3
Helixi286 – 290Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LD2model-A1-303[»]
2W96X-ray2.30B1-303[»]
2W99X-ray2.80B1-303[»]
2W9FX-ray2.85B1-303[»]
2W9ZX-ray2.45B1-303[»]
3G33X-ray3.00A/C1-303[»]
5FWKelectron microscopy3.90K1-303[»]
5FWLelectron microscopy9.00K1-303[»]
5FWMelectron microscopy8.00K1-303[»]
5FWPelectron microscopy7.20K1-303[»]
ProteinModelPortaliP11802
SMRiP11802
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP11802

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini6 – 295Protein kinasePROSITE-ProRule annotationAdd BLAST290

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni50 – 56Required for binding D-type cyclins7

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi42 – 48Poly-Gly7

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0594 Eukaryota
ENOG410XPP3 LUCA
GeneTreeiENSGT00910000144030
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP11802
KOiK02089
OMAiATPRYEP
OrthoDBiEOG091G0I1Q
PhylomeDBiP11802
TreeFamiTF101022

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P11802-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MATSRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGGGGGGLP
60 70 80 90 100
ISTVREVALL RRLEAFEHPN VVRLMDVCAT SRTDREIKVT LVFEHVDQDL
110 120 130 140 150
RTYLDKAPPP GLPAETIKDL MRQFLRGLDF LHANCIVHRD LKPENILVTS
160 170 180 190 200
GGTVKLADFG LARIYSYQMA LTPVVVTLWY RAPEVLLQST YATPVDMWSV
210 220 230 240 250
GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR DVSLPRGAFP
260 270 280 290 300
PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKDEG

NPE
Length:303
Mass (Da):33,730
Last modified:November 1, 1995 - v2
Checksum:i0916A0C07403A33A
GO
Isoform 2 (identifier: P11802-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-120: Missing.

Note: No experimental confirmation available.
Show »
Length:183
Mass (Da):20,725
Checksum:i4CD51FFCEAD58E5B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti117I → L in BAG36447 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00620024R → C in CMM3; somatic and familial; generates a dominant oncogene resistant to inhibition by p16(INK4a). 2 PublicationsCorresponds to variant dbSNP:rs11547328Ensembl.1
Natural variantiVAR_00620124R → H in CMM3. 1 PublicationCorresponds to variant dbSNP:rs104894340Ensembl.1
Natural variantiVAR_02115241N → S in CMM3; sporadic. 1 PublicationCorresponds to variant dbSNP:rs144890720Ensembl.1
Natural variantiVAR_02915382R → Q1 PublicationCorresponds to variant dbSNP:rs3211612Ensembl.1
Natural variantiVAR_041976122R → H1 PublicationCorresponds to variant dbSNP:rs34386532Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0564871 – 120Missing in isoform 2. 1 PublicationAdd BLAST120

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M14505 mRNA Translation: AAA35673.1
U81031 Genomic DNA Translation: AAC39521.2
Z48970 mRNA Translation: CAA88834.1
U37022 Genomic DNA Translation: AAC50506.1
AF507942 Genomic DNA Translation: AAM23014.1
AK297901 mRNA Translation: BAG60221.1
AK313701 mRNA Translation: BAG36447.1
CR407668 mRNA Translation: CAG28596.1
CR542247 mRNA Translation: CAG47043.1
AC025165 Genomic DNA No translation available.
CH471054 Genomic DNA Translation: EAW97058.1
BC003644 mRNA Translation: AAH03644.1
BC005864 mRNA Translation: AAH05864.1
BC010153 mRNA Translation: AAH10153.1
S67448 Genomic DNA Translation: AAD13991.1
CCDSiCCDS8953.1 [P11802-1]
PIRiI52695
S52841
RefSeqiNP_000066.1, NM_000075.3 [P11802-1]
UniGeneiHs.95577

Genome annotation databases

EnsembliENST00000257904; ENSP00000257904; ENSG00000135446 [P11802-1]
GeneIDi1019
KEGGihsa:1019
UCSCiuc001spv.4 human [P11802-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCDK4_HUMAN
AccessioniPrimary (citable) accession number: P11802
Secondary accession number(s): B2R9A0
, B4DNF9, O00576, Q6FG61
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: November 1, 1995
Last modified: April 25, 2018
This is version 219 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health