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P30285 (CDK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase 4

EC=2.7.11.22
Alternative name(s):
CRK3
Cell division protein kinase 4
PSK-J3
Gene names
Name:Cdk4
Synonyms:Crk3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length303 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

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 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.

Catalytic activity

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

Enzyme regulation

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.

Subunit 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 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. Ref.6 Ref.7

Subcellular location

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.

Post-translational modification

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. Ref.5

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Cell division
   Cellular componentCytoplasm
Membrane
Nucleus
   DiseaseProto-oncogene
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG1/S transition of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

cell division

Inferred from electronic annotation. Source: UniProtKB-KW

circadian rhythm

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell cycle arrest

Inferred from sequence or structural similarity. Source: UniProtKB

organ regeneration

Inferred from electronic annotation. Source: Ensembl

positive regulation of G2/M transition of mitotic cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell size

Inferred from electronic annotation. Source: Ensembl

positive regulation of fibroblast proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of translation

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay PubMed 12124778PubMed 12588994. Source: MGI

regulation of cell cycle

Inferred from direct assay PubMed 12588994. Source: MGI

regulation of cell proliferation

Inferred from mutant phenotype PubMed 12917627. Source: MGI

response to drug

Inferred from electronic annotation. Source: Ensembl

response to hyperoxia

Inferred from electronic annotation. Source: Ensembl

response to lead ion

Inferred from electronic annotation. Source: Ensembl

response to testosterone

Inferred from electronic annotation. Source: Ensembl

response to toxic substance

Inferred from electronic annotation. Source: Ensembl

signal transduction

Inferred from direct assay PubMed 12130539. Source: MGI

   Cellular_componentchromatin

Inferred from electronic annotation. Source: Ensembl

cyclin-dependent protein kinase holoenzyme complex

Inferred from physical interaction PubMed 12970760. Source: MGI

cytosol

Inferred from electronic annotation. Source: Ensembl

nuclear membrane

Inferred from electronic annotation. Source: Ensembl

nucleolus

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 10082561PubMed 12917627PubMed 15645444PubMed 21411630PubMed 8988060. Source: MGI

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: Ensembl

transcription factor complex

Inferred from direct assay PubMed 10082561. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 12970171PubMed 12970760. Source: MGI

kinase activity

Inferred from direct assay PubMed 12124778. Source: MGI

protein kinase activity

Inferred from direct assay PubMed 12130539PubMed 12588994PubMed 21508411. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

CCND1P243852EBI-847225,EBI-375001From a different organism.
Ccnd1P2532213EBI-847225,EBI-847243
RB1P064002EBI-847225,EBI-491274From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 303302Cyclin-dependent kinase 4
PRO_0000085779

Regions

Domain6 – 295290Protein kinase
Nucleotide binding12 – 209ATP By similarity
Region50 – 567Required for binding D-type cyclins By similarity

Sites

Active site1401Proton acceptor By similarity
Binding site351ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue1721Phosphothreonine; by CAK Ref.5

Sequences

Sequence LengthMass (Da)Tools
P30285 [UniParc].

Last modified April 1, 1993. Version 1.
Checksum: CB4F42A8AA13634A

FASTA30333,751
        10         20         30         40         50         60 
MAATRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP VSTVREVALL 

        70         80         90        100        110        120 
RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL RTYLDKAPPP GLPVETIKDL 

       130        140        150        160        170        180 
MRQFLSGLDF LHANCIVHRD LKPENILVTS NGTVKLADFG LARIYSYQMA LTPVVVTLWY 

       190        200        210        220        230        240 
RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR 

       250        260        270        280        290        300 
EVSLPRGAFA PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKEES 


DAE 

« Hide

References

« Hide 'large scale' references
[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]"Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)."
Sugimoto M., Nakamura T., Ohtani N., Hampson L., Hampson I.N., Shimamoto A., Furuichi Y., Okumura K., Niwa S., Taya Y., Hara E.
Genes Dev. 13:3027-3033(1999) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
PIRA44293.
RefSeqNP_034000.1. NM_009870.3.
UniGeneMm.6839.

3D structure databases

ProteinModelPortalP30285.
SMRP30285. Positions 5-295.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198645. 23 interactions.
DIPDIP-194N.
IntActP30285. 12 interactions.
MINTMINT-4090398.

Chemistry

BindingDBP30285.
ChEMBLCHEMBL2134.

PTM databases

PhosphoSiteP30285.

Proteomic databases

PaxDbP30285.
PRIDEP30285.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728.
GeneID12567.
KEGGmmu:12567.
UCSCuc007hhv.2. mouse.

Organism-specific databases

CTD1019.
MGIMGI:88357. Cdk4.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP30285.
KOK02089.
OMAYLQKAEG.
OrthoDBEOG73JKVV.
PhylomeDBP30285.
TreeFamTF101022.

Enzyme and pathway databases

BRENDA2.7.11.22. 3474.
ReactomeREACT_188804. Cell Cycle.
REACT_198624. Meiosis.
REACT_27235. Meiotic Recombination.

Gene expression databases

ArrayExpressP30285.
BgeeP30285.
CleanExMM_CDK4.
GenevestigatorP30285.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio281662.
PROP30285.
SOURCESearch...

Entry information

Entry nameCDK4_MOUSE
AccessionPrimary (citable) accession number: P30285
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: April 16, 2014
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot