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Protein

Cyclin-dependent kinase 4

Gene

Cdk4

Organism
Mus musculus (Mouse)
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 (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 subsequent activation.By similarity

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-containing complex binding 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: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of cell size Source: MGI
  • positive regulation of fibroblast proliferation Source: MGI
  • positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
  • positive regulation of translation Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of cell cycle Source: MGI
  • regulation of cell proliferation Source: MGI
  • regulation of G2/M transition of mitotic cell cycle Source: GO_Central
  • 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 hyperoxia Source: Ensembl
  • response to lead ion Source: MGI
  • response to organic substance Source: MGI
  • response to testosterone Source: MGI
  • response to toxic substance Source: Ensembl
  • signal transduction Source: MGI

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 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-8878166 Transcriptional regulation by RUNX2

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:88357 Cdk4

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

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
SwissPalmiP30285

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

Binary interactionsi

Show more details

GO - Molecular functioni

  • cyclin binding Source: MGI

Protein-protein interaction databases

BioGridi198645, 22 interactors
ComplexPortaliCPX-2073 cyclin D1-CDK4 complex
CPX-2074 Cyclin D2-CDK4 complex
CPX-2077 Cyclin D3-CDK4 complex
CORUMiP30285
DIPiDIP-194N
IntActiP30285, 16 interactors
MINTiP30285
STRINGi10090.ENSMUSP00000006911

Chemistry databases

BindingDBiP30285

Structurei

3D structure databases

ProteinModelPortaliP30285
SMRiP30285
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

Phylogenomic databases

eggNOGiKOG0594 Eukaryota
ENOG410XPP3 LUCA
GeneTreeiENSGT00910000144030
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP30285
KOiK02089
OMAiATPRYEP
OrthoDBiEOG091G0I1Q
PhylomeDBiP30285
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

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

Similar proteinsi

Entry informationi

Entry nameiCDK4_MOUSE
AccessioniPrimary (citable) accession number: P30285
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: June 20, 2018
This is version 178 of the entry and version 1 of the sequence. See 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

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