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Protein

Cyclin-dependent kinase 4

Gene

Cdk4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

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 subsequennt activation.

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: MGI
  • cyclin-dependent protein serine/threonine kinase activity Source: MGI
  • kinase activity Source: MGI
  • protein kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: MGI

GO - Biological processi

  • adipose tissue development Source: MGI
  • animal organ regeneration Source: Ensembl
  • cell division Source: UniProtKB-KW
  • cellular response to insulin stimulus Source: MGI
  • cellular response to interleukin-4 Source: MGI
  • cellular response to ionomycin Source: MGI
  • cellular response to lipopolysaccharide Source: MGI
  • cellular response to phorbol 13-acetate 12-myristate Source: MGI
  • circadian rhythm Source: Ensembl
  • G1/S transition of mitotic cell cycle Source: MGI
  • lens development in camera-type eye Source: Ensembl
  • negative regulation of cell cycle arrest Source: UniProtKB
  • positive regulation of apoptotic process Source: Ensembl
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of cell size Source: Ensembl
  • positive regulation of fibroblast proliferation Source: MGI
  • positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
  • positive regulation of translation Source: Ensembl
  • protein phosphorylation Source: MGI
  • regulation of cell cycle Source: MGI
  • regulation of cell proliferation Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of insulin receptor signaling pathway Source: MGI
  • regulation of lipid biosynthetic process Source: MGI
  • regulation of lipid catabolic process Source: MGI
  • regulation of multicellular organism growth Source: MGI
  • response to drug Source: MGI
  • response to hyperoxia Source: Ensembl
  • response to lead ion Source: Ensembl
  • response to testosterone Source: Ensembl
  • response to toxic substance Source: Ensembl
  • signal transduction Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, Cell division

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22. 3474.
ReactomeiR-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559585. Oncogene Induced Senescence.
R-MMU-3214858. RMTs methylate histone arginines.
R-MMU-69229. Ubiquitin-dependent degradation of Cyclin D1.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-8849470. PTK6 Regulates Cell Cycle.
R-MMU-912446. Meiotic recombination.
R-MMU-912497. Meiotic Recombination.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 4 (EC:2.7.11.22)
Alternative name(s):
CRK3
Cell division protein kinase 4
PSK-J3
Gene namesi
Name:Cdk4
Synonyms:Crk3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:88357. Cdk4.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity
  • Membrane By similarity

  • 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 (By similarity).By similarity

GO - Cellular componenti

  • bicellular tight junction Source: Ensembl
  • chromatin Source: MGI
  • cyclin D2-CDK4 complex Source: MGI
  • cyclin-dependent protein kinase holoenzyme complex Source: MGI
  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • nuclear membrane Source: MGI
  • nucleolus Source: MGI
  • nucleoplasm Source: Reactome
  • nucleus Source: MGI
  • perinuclear region of cytoplasm Source: Ensembl
  • protein complex Source: MGI
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL2134.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000857792 – 303Cyclin-dependent kinase 4Add BLAST302

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Modified residuei172Phosphothreonine; by CAK1 Publication1
Modified residuei300PhosphoserineBy similarity1

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 (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP30285.
PaxDbiP30285.
PeptideAtlasiP30285.
PRIDEiP30285.

PTM databases

iPTMnetiP30285.
PhosphoSitePlusiP30285.

Expressioni

Gene expression databases

BgeeiENSMUSG00000006728.
CleanExiMM_CDK4.
ExpressionAtlasiP30285. baseline and differential.
GenevisibleiP30285. MM.

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 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 (By similarity). Interacts with SEI1 and CCND1. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (By similarity).By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CCND1P243852EBI-847225,EBI-375001From a different organism.
Ccnd1P2532213EBI-847225,EBI-847243
RB1P064002EBI-847225,EBI-491274From a different organism.

GO - Molecular functioni

  • cyclin binding Source: MGI

Protein-protein interaction databases

BioGridi198645. 22 interactors.
DIPiDIP-194N.
IntActiP30285. 12 interactors.
MINTiMINT-4090398.
STRINGi10090.ENSMUSP00000006911.

Chemistry databases

BindingDBiP30285.

Structurei

3D structure databases

ProteinModelPortaliP30285.
ModBaseiSearch...
MobiDBiSearch...

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 cyclinsBy similarity7

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0594. Eukaryota.
ENOG410XPP3. LUCA.
GeneTreeiENSGT00830000128256.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP30285.
KOiK02089.
OMAiKRPKDFC.
OrthoDBiEOG091G0I1Q.
PhylomeDBiP30285.
TreeFamiTF101022.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

P30285-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAATRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP
60 70 80 90 100
VSTVREVALL RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL
110 120 130 140 150
RTYLDKAPPP GLPVETIKDL MRQFLSGLDF LHANCIVHRD LKPENILVTS
160 170 180 190 200
NGTVKLADFG LARIYSYQMA LTPVVVTLWY RAPEVLLQST YATPVDMWSV
210 220 230 240 250
GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR EVSLPRGAFA
260 270 280 290 300
PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKEES

DAE
Length:303
Mass (Da):33,751
Last modified:April 1, 1993 - v1
Checksum:iCB4F42A8AA13634A
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L01640 mRNA. Translation: AAA37646.1.
BC046336 mRNA. Translation: AAH46336.1.
BC052694 mRNA. Translation: AAH52694.1.
X57238 mRNA. Translation: CAA40514.1.
X65069 mRNA. Translation: CAA46202.1.
CCDSiCCDS24226.1.
PIRiA44293.
RefSeqiNP_034000.1. NM_009870.3.
UniGeneiMm.6839.

Genome annotation databases

EnsembliENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728.
GeneIDi12567.
KEGGimmu:12567.
UCSCiuc007hhv.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L01640 mRNA. Translation: AAA37646.1.
BC046336 mRNA. Translation: AAH46336.1.
BC052694 mRNA. Translation: AAH52694.1.
X57238 mRNA. Translation: CAA40514.1.
X65069 mRNA. Translation: CAA46202.1.
CCDSiCCDS24226.1.
PIRiA44293.
RefSeqiNP_034000.1. NM_009870.3.
UniGeneiMm.6839.

3D structure databases

ProteinModelPortaliP30285.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198645. 22 interactors.
DIPiDIP-194N.
IntActiP30285. 12 interactors.
MINTiMINT-4090398.
STRINGi10090.ENSMUSP00000006911.

Chemistry databases

BindingDBiP30285.
ChEMBLiCHEMBL2134.

PTM databases

iPTMnetiP30285.
PhosphoSitePlusiP30285.

Proteomic databases

EPDiP30285.
PaxDbiP30285.
PeptideAtlasiP30285.
PRIDEiP30285.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728.
GeneIDi12567.
KEGGimmu:12567.
UCSCiuc007hhv.2. mouse.

Organism-specific databases

CTDi1019.
MGIiMGI:88357. Cdk4.

Phylogenomic databases

eggNOGiKOG0594. Eukaryota.
ENOG410XPP3. LUCA.
GeneTreeiENSGT00830000128256.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP30285.
KOiK02089.
OMAiKRPKDFC.
OrthoDBiEOG091G0I1Q.
PhylomeDBiP30285.
TreeFamiTF101022.

Enzyme and pathway databases

BRENDAi2.7.11.22. 3474.
ReactomeiR-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559585. Oncogene Induced Senescence.
R-MMU-3214858. RMTs methylate histone arginines.
R-MMU-69229. Ubiquitin-dependent degradation of Cyclin D1.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-8849470. PTK6 Regulates Cell Cycle.
R-MMU-912446. Meiotic recombination.
R-MMU-912497. Meiotic Recombination.

Miscellaneous databases

PROiP30285.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000006728.
CleanExiMM_CDK4.
ExpressionAtlasiP30285. baseline and differential.
GenevisibleiP30285. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCDK4_MOUSE
AccessioniPrimary (citable) accession number: P30285
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: November 30, 2016
This is version 164 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.