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Database: UniProt
Entry: P30285
LinkDB: P30285
Original site: P30285 
ID   CDK4_MOUSE              Reviewed;         303 AA.
AC   P30285;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1993, sequence version 1.
DT   03-SEP-2014, entry version 142.
DE   RecName: Full=Cyclin-dependent kinase 4;
DE            EC=2.7.11.22;
DE   AltName: Full=CRK3;
DE   AltName: Full=Cell division protein kinase 4;
DE   AltName: Full=PSK-J3;
GN   Name=Cdk4; Synonyms=Crk3;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi;
OC   Muroidea; Muridae; Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND CATALYTIC ACTIVITY.
RX   PubMed=1423597; DOI=10.1016/0092-8674(92)90360-O;
RA   Matsushime H., Ewen M.E., Strom D.K., Kato J.Y., Hanks S.K.,
RA   Roussel M.F., Sherr C.J.;
RT   "Identification and properties of an atypical catalytic subunit
RT   (p34PSK-J3/cdk4) for mammalian D type G1 cyclins.";
RL   Cell 71:323-334(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6; TISSUE=Olfactory epithelium;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 142-188.
RC   STRAIN=C57BL/6; TISSUE=Embryonic brain;
RX   PubMed=1281307;
RA   Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G.,
RA   Chestier A., Wilkinson D.G., Charnay P.;
RT   "An Eph-related receptor protein tyrosine kinase gene segmentally
RT   expressed in the developing mouse hindbrain.";
RL   Oncogene 7:2499-2506(1992).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 144-178.
RC   STRAIN=CBA; TISSUE=Bone marrow;
RX   PubMed=8444355; DOI=10.1016/0378-1119(93)90411-U;
RA   Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V.;
RT   "Novel CDC2-related protein kinases produced in murine hematopoietic
RT   stem cells.";
RL   Gene 124:305-306(1993).
RN   [5]
RP   PHOSPHORYLATION AT THR-172.
RX   PubMed=8139570; DOI=10.1128/MCB.14.4.2713;
RA   Kato J.-Y., Matsuoka M., Strom D.K., Sherr C.J.;
RT   "Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating
RT   kinase.";
RL   Mol. Cell. Biol. 14:2713-2721(1994).
RN   [6]
RP   INTERACTION WITH SEI1.
RX   PubMed=10580009; DOI=10.1101/gad.13.22.3027;
RA   Sugimoto M., Nakamura T., Ohtani N., Hampson L., Hampson I.N.,
RA   Shimamoto A., Furuichi Y., Okumura K., Niwa S., Taya Y., Hara E.;
RT   "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-
RT   1).";
RL   Genes Dev. 13:3027-3033(1999).
RN   [7]
RP   INTERACTION WITH CCND1.
RX   PubMed=19767775; DOI=10.1038/onc.2009.287;
RA   Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.;
RT   "Lysine 269 is essential for cyclin D1 ubiquitylation by the
RT   SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent
RT   degradation.";
RL   Oncogene 28:4317-4325(2009).
CC   -!- FUNCTION: Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes
CC       that phosphorylate and inhibit members of the retinoblastoma (RB)
CC       protein family including RB1 and regulate the cell-cycle during
CC       G(1)/S transition. Phosphorylation of RB1 allows dissociation of
CC       the transcription factor E2F from the RB/E2F complexes and the
CC       subsequent transcription of E2F target genes which are responsible
CC       for the progression through the G(1) phase. Hypophosphorylates RB1
CC       in early G(1) phase. Cyclin D-CDK4 complexes are major integrators
CC       of various mitogenenic and antimitogenic signals. Also
CC       phosphorylates SMAD3 in a cell-cycle-dependent manner and
CC       represses its transcriptional activity. Component of the ternary
CC       complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation
CC       and activity of the cyclin D-CDK4 complex (By similarity).
CC   -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC   -!- ENZYME REGULATION: Both phosphorylation at Thr-172 and binding of
CC       a D-type cyclin are necessary for enzymatic activity. Full
CC       activation of the cyclin-D-CDK4 complex appears to require other
CC       factors such as recruitment of the substrate via a substrate
CC       recruitment motif, and/or formation of the CDKN1B ternary complex.
CC       Inhibited by INK4 family members. In resting cells, the non-
CC       tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at
CC       Thr-172 and inactivation, while, in proliferating cells, tyrosine
CC       phosphorylation of CDKN1B allows phosphorylation of Thr-172 of
CC       CDK4 and subsequennt activation.
CC   -!- SUBUNIT: Component of the D-CDK4 complex, composed of CDK4 and
CC       some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly
CC       in the complex with CCND1, CCND2 or CCND3. Interacts with ZNF655.
CC       Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in
CC       modulating CDK4 enzymatic activity. Interacts directly with CDKN1B
CC       (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows
CC       assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation,
CC       nuclear translocation and enhances the cyclin D-CDK4 complex
CC       activity. CDK4 activity is either inhibited or enhanced depending
CC       on stoichiometry of complex. The non-tyrosine-phosphorylated form
CC       of CDKN1B prevents T-loop phosphorylation of CDK4 producing
CC       inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also
CC       forms ternary complexes with CDKN1A or CDKN2A. Interacts directly
CC       with CDKN1A (via its N-terminal); the interaction promotes the
CC       assembly of the cyclin D-CDK4 complex, its nuclear translocation
CC       and promotes the cyclin D-dependent enzyme activity of CDK4.
CC       Interacts with CCND1; the interaction is prevented with the
CC       binding of CCND1 to INSM1 during cell cycle progression (By
CC       similarity). Interacts with SEI1 and CCND1.
CC   -!- INTERACTION:
CC       P24385:CCND1 (xeno); NbExp=2; IntAct=EBI-847225, EBI-375001;
CC       P25322:Ccnd1; NbExp=13; IntAct=EBI-847225, EBI-847243;
CC       P06400:RB1 (xeno); NbExp=2; IntAct=EBI-847225, EBI-491274;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By
CC       similarity). Membrane (By similarity). Note=Cytoplasmic when non-
CC       complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells
CC       progress through G(1) phase. The complex accumulates on the
CC       nuclear membrane and enters the nucleus on transition from G(1) to
CC       S phase. Also present in nucleoli and heterochromatin lumps.
CC       Colocalizes with RB1 after release into the nucleus (By
CC       similarity).
CC   -!- PTM: Phosphorylation at Thr-172 is required for enzymatic
CC       activity. Phosphorylated, in vitro, at this site by CCNH-CDK7,
CC       but, in vivo, appears to be phosphorylated by a proline-directed
CC       kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation
CC       and consequent CDK4 enzyme activity, is dependent on the tyrosine
CC       phosphorylation state of CDKN1B. Thus, in proliferating cells,
CC       CDK4 within the complex is phosphorylated on Thr-172 in the T-
CC       loop. In resting cells, phosphorylation on Thr-172 is prevented by
CC       the non-tyrosine-phosphorylated form of CDKN1B (By similarity).
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC       Ser/Thr protein kinase family. CDC2/CDKX subfamily.
CC   -!- SIMILARITY: Contains 1 protein kinase domain.
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DR   EMBL; L01640; AAA37646.1; -; mRNA.
DR   EMBL; BC046336; AAH46336.1; -; mRNA.
DR   EMBL; BC052694; AAH52694.1; -; mRNA.
DR   EMBL; X57238; CAA40514.1; -; mRNA.
DR   EMBL; X65069; CAA46202.1; -; mRNA.
DR   CCDS; CCDS24226.1; -.
DR   PIR; A44293; A44293.
DR   RefSeq; NP_034000.1; NM_009870.3.
DR   UniGene; Mm.6839; -.
DR   ProteinModelPortal; P30285; -.
DR   SMR; P30285; 5-295.
DR   BioGrid; 198645; 23.
DR   DIP; DIP-194N; -.
DR   IntAct; P30285; 12.
DR   MINT; MINT-4090398; -.
DR   BindingDB; P30285; -.
DR   ChEMBL; CHEMBL2134; -.
DR   PhosphoSite; P30285; -.
DR   MaxQB; P30285; -.
DR   PaxDb; P30285; -.
DR   PRIDE; P30285; -.
DR   Ensembl; ENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728.
DR   GeneID; 12567; -.
DR   KEGG; mmu:12567; -.
DR   UCSC; uc007hhv.2; mouse.
DR   CTD; 1019; -.
DR   MGI; MGI:88357; Cdk4.
DR   eggNOG; COG0515; -.
DR   HOGENOM; HOG000233024; -.
DR   HOVERGEN; HBG014652; -.
DR   InParanoid; P30285; -.
DR   KO; K02089; -.
DR   OMA; IDQDLRT; -.
DR   OrthoDB; EOG73JKVV; -.
DR   PhylomeDB; P30285; -.
DR   TreeFam; TF101022; -.
DR   BRENDA; 2.7.11.22; 3474.
DR   Reactome; REACT_188970; Oxidative Stress Induced Senescence.
DR   Reactome; REACT_188971; Oncogene Induced Senescence.
DR   Reactome; REACT_198629; Meiotic recombination.
DR   Reactome; REACT_206033; Senescence-Associated Secretory Phenotype (SASP).
DR   Reactome; REACT_27235; Meiotic Recombination.
DR   NextBio; 281662; -.
DR   PRO; PR:P30285; -.
DR   ArrayExpress; P30285; -.
DR   Bgee; P30285; -.
DR   CleanEx; MM_CDK4; -.
DR   Genevestigator; P30285; -.
DR   GO; GO:0000785; C:chromatin; IEA:Ensembl.
DR   GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:MGI.
DR   GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR   GO; GO:0031965; C:nuclear membrane; IEA:Ensembl.
DR   GO; GO:0005730; C:nucleolus; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:MGI.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR   GO; GO:0005667; C:transcription factor complex; IDA:MGI.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:MGI.
DR   GO; GO:0016301; F:kinase activity; IDA:MGI.
DR   GO; GO:0005515; F:protein binding; IPI:UniProtKB.
DR   GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR   GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IEA:Ensembl.
DR   GO; GO:0071157; P:negative regulation of cell cycle arrest; ISS:UniProtKB.
DR   GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0045793; P:positive regulation of cell size; IEA:Ensembl.
DR   GO; GO:0048146; P:positive regulation of fibroblast proliferation; IEA:Ensembl.
DR   GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; ISS:UniProtKB.
DR   GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR   GO; GO:0051726; P:regulation of cell cycle; IDA:MGI.
DR   GO; GO:0042127; P:regulation of cell proliferation; IMP:MGI.
DR   GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR   GO; GO:0055093; P:response to hyperoxia; IEA:Ensembl.
DR   GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR   GO; GO:0033574; P:response to testosterone; IEA:Ensembl.
DR   GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; IDA:MGI.
DR   InterPro; IPR011009; Kinase-like_dom.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   Acetylation; ATP-binding; Cell cycle; Cell division;
KW   Complete proteome; Cytoplasm; Kinase; Membrane; Nucleotide-binding;
KW   Nucleus; Phosphoprotein; Proto-oncogene; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase.
FT   INIT_MET      1      1       Removed (By similarity).
FT   CHAIN         2    303       Cyclin-dependent kinase 4.
FT                                /FTId=PRO_0000085779.
FT   DOMAIN        6    295       Protein kinase.
FT   NP_BIND      12     20       ATP (By similarity).
FT   REGION       50     56       Required for binding D-type cyclins (By
FT                                similarity).
FT   ACT_SITE    140    140       Proton acceptor (By similarity).
FT   BINDING      35     35       ATP (By similarity).
FT   MOD_RES       2      2       N-acetylalanine (By similarity).
FT   MOD_RES     172    172       Phosphothreonine; by CAK.
SQ   SEQUENCE   303 AA;  33751 MW;  CB4F42A8AA13634A CRC64;
     MAATRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP VSTVREVALL
     RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL RTYLDKAPPP GLPVETIKDL
     MRQFLSGLDF LHANCIVHRD LKPENILVTS NGTVKLADFG LARIYSYQMA LTPVVVTLWY
     RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR
     EVSLPRGAFA PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKEES
     DAE
//
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