ID CDK4_MOUSE Reviewed; 303 AA.
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1993, sequence version 1.
DT 13-NOV-2013, entry version 133.
DE RecName: Full=Cyclin-dependent kinase 4;
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.
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).
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).
RP NUCLEOTIDE SEQUENCE [MRNA] OF 142-188.
RC STRAIN=C57BL/6; TISSUE=Embryonic brain;
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).
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).
RP PHOSPHORYLATION AT THR-172.
RA Kato J.-Y., Matsuoka M., Strom D.K., Sherr C.J.;
RT "Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating
RL Mol. Cell. Biol. 14:2713-2721(1994).
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-
RL Genes Dev. 13:3027-3033(1999).
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
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 (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 -!- 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 IPI; IPI00128326; -.
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 DIP; DIP-194N; -.
DR IntAct; P30285; 12.
DR MINT; MINT-4090398; -.
DR PhosphoSite; 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; YLQKAEG; -.
DR OrthoDB; EOG73JKVV; -.
DR BRENDA; 126.96.36.199; 3474.
DR Reactome; REACT_118161; Cell Cycle.
DR Reactome; REACT_120463; Meiosis.
DR Reactome; REACT_27235; Meiotic Recombination.
DR BindingDB; P30285; -.
DR ChEMBL; CHEMBL2134; -.
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: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:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IEA:Ensembl.
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:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; 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 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 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