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P30285

- CDK4_MOUSE

UniProt

P30285 - CDK4_MOUSE

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Protein

Cyclin-dependent kinase 4

Gene

Cdk4

Organism
Mus musculus (Mouse)
Status
Reviewed - 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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei35 – 351ATPPROSITE-ProRule annotation
Active sitei140 – 1401Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi12 – 209ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. cyclin-dependent protein serine/threonine kinase activity Source: MGI
  3. kinase activity Source: MGI
  4. protein kinase activity Source: MGI

GO - Biological processi

  1. cell division Source: UniProtKB-KW
  2. circadian rhythm Source: Ensembl
  3. G1/S transition of mitotic cell cycle Source: Ensembl
  4. negative regulation of cell cycle arrest Source: UniProtKB
  5. organ regeneration Source: Ensembl
  6. positive regulation of apoptotic process Source: Ensembl
  7. positive regulation of cell size Source: Ensembl
  8. positive regulation of fibroblast proliferation Source: Ensembl
  9. positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
  10. positive regulation of translation Source: Ensembl
  11. protein phosphorylation Source: MGI
  12. regulation of cell cycle Source: MGI
  13. regulation of cell proliferation Source: MGI
  14. response to drug Source: Ensembl
  15. response to hyperoxia Source: Ensembl
  16. response to lead ion Source: Ensembl
  17. response to testosterone Source: Ensembl
  18. response to toxic substance Source: Ensembl
  19. 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.
ReactomeiREACT_188970. Oxidative Stress Induced Senescence.
REACT_188971. Oncogene Induced Senescence.
REACT_198629. Meiotic recombination.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_244207. RMTs methylate histone arginines.
REACT_252217. Transcriptional regulation of white adipocyte differentiation.
REACT_258573. Cyclin D associated events in G1.
REACT_263467. Ubiquitin-dependent degradation of Cyclin D1.
REACT_27235. 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
ProteomesiUP000000589: 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

  1. chromatin Source: Ensembl
  2. cyclin-dependent protein kinase holoenzyme complex Source: MGI
  3. cytosol Source: Ensembl
  4. nuclear membrane Source: Ensembl
  5. nucleolus Source: Ensembl
  6. nucleoplasm Source: Reactome
  7. nucleus Source: MGI
  8. perinuclear region of cytoplasm Source: Ensembl
  9. transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 303302Cyclin-dependent kinase 4PRO_0000085779Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanineBy similarity
Modified residuei172 – 1721Phosphothreonine; by CAK1 Publication

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

MaxQBiP30285.
PaxDbiP30285.
PRIDEiP30285.

PTM databases

PhosphoSiteiP30285.

Expressioni

Gene expression databases

BgeeiP30285.
CleanExiMM_CDK4.
ExpressionAtlasiP30285. baseline and differential.
GenevestigatoriP30285.

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.By similarity2 Publications

Binary interactionsi

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

Protein-protein interaction databases

BioGridi198645. 23 interactions.
DIPiDIP-194N.
IntActiP30285. 12 interactions.
MINTiMINT-4090398.

Structurei

3D structure databases

ProteinModelPortaliP30285.
SMRiP30285. Positions 5-295.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini6 – 295290Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni50 – 567Required for binding D-type cyclinsBy similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP30285.
KOiK02089.
OMAiIDQDLRT.
OrthoDBiEOG73JKVV.
PhylomeDBiP30285.
TreeFamiTF101022.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
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 .
CCDSi CCDS24226.1.
PIRi A44293.
RefSeqi NP_034000.1. NM_009870.3.
UniGenei Mm.6839.

3D structure databases

ProteinModelPortali P30285.
SMRi P30285. Positions 5-295.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 198645. 23 interactions.
DIPi DIP-194N.
IntActi P30285. 12 interactions.
MINTi MINT-4090398.

Chemistry

BindingDBi P30285.
ChEMBLi CHEMBL2134.

PTM databases

PhosphoSitei P30285.

Proteomic databases

MaxQBi P30285.
PaxDbi P30285.
PRIDEi P30285.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000006911 ; ENSMUSP00000006911 ; ENSMUSG00000006728 .
GeneIDi 12567.
KEGGi mmu:12567.
UCSCi uc007hhv.2. mouse.

Organism-specific databases

CTDi 1019.
MGIi MGI:88357. Cdk4.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000233024.
HOVERGENi HBG014652.
InParanoidi P30285.
KOi K02089.
OMAi IDQDLRT.
OrthoDBi EOG73JKVV.
PhylomeDBi P30285.
TreeFami TF101022.

Enzyme and pathway databases

BRENDAi 2.7.11.22. 3474.
Reactomei REACT_188970. Oxidative Stress Induced Senescence.
REACT_188971. Oncogene Induced Senescence.
REACT_198629. Meiotic recombination.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_244207. RMTs methylate histone arginines.
REACT_252217. Transcriptional regulation of white adipocyte differentiation.
REACT_258573. Cyclin D associated events in G1.
REACT_263467. Ubiquitin-dependent degradation of Cyclin D1.
REACT_27235. Meiotic Recombination.

Miscellaneous databases

NextBioi 281662.
PROi P30285.
SOURCEi Search...

Gene expression databases

Bgeei P30285.
CleanExi MM_CDK4.
ExpressionAtlasi P30285. baseline and differential.
Genevestigatori P30285.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins."
    Matsushime H., Ewen M.E., Strom D.K., Kato J.Y., Hanks S.K., Roussel M.F., Sherr C.J.
    Cell 71:323-334(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6.
    Tissue: Olfactory epithelium.
  3. "An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain."
    Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A., Wilkinson D.G., Charnay P.
    Oncogene 7:2499-2506(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 142-188.
    Strain: C57BL/6.
    Tissue: Embryonic brain.
  4. "Novel CDC2-related protein kinases produced in murine hematopoietic stem cells."
    Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V.
    Gene 124:305-306(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 144-178.
    Strain: CBA.
    Tissue: Bone marrow.
  5. "Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase."
    Kato J.-Y., Matsuoka M., Strom D.K., Sherr C.J.
    Mol. Cell. Biol. 14:2713-2721(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-172.
  6. Cited for: INTERACTION WITH SEI1.
  7. "Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation."
    Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.
    Oncogene 28:4317-4325(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CCND1.

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 26, 2014
This is version 145 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

External Data

Dasty 3