CDK4_MOUSE
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-AUG-2022, entry version 202.
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; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC 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., Roussel M.F.,
RA Sherr C.J.;
RT "Identification and properties of an atypical catalytic subunit (p34PSK-
RT 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/6J; 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 142-188.
RC STRAIN=C57BL/6J; TISSUE=Embryonic brain;
RX PubMed=1281307;
RA Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A.,
RA Wilkinson D.G., Charnay P.;
RT "An Eph-related receptor protein tyrosine kinase gene segmentally expressed
RT in the developing mouse hindbrain.";
RL Oncogene 7:2499-2506(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 144-178.
RC STRAIN=CBA/J; 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 stem
RT cells.";
RL Gene 124:305-306(1993).
RN [5]
RP PHOSPHORYLATION AT THR-172.
RX PubMed=8139570; DOI=10.1128/mcb.14.4.2713-2721.1994;
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-1).";
RL Genes Dev. 13:3027-3033(1999).
RN [7]
RP INTERACTION WITH CEBPA.
RX PubMed=15107404; DOI=10.1101/gad.1183304;
RA Wang G.L., Iakova P., Wilde M., Awad S., Timchenko N.A.;
RT "Liver tumors escape negative control of proliferation via PI3K/Akt-
RT mediated block of C/EBP alpha growth inhibitory activity.";
RL Genes Dev. 18:912-925(2004).
RN [8]
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).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that
CC phosphorylate and inhibit members of the retinoblastoma (RB) protein
CC family including RB1 and regulate the cell-cycle during G(1)/S
CC transition. Phosphorylation of RB1 allows dissociation of the
CC transcription factor E2F from the RB/E2F complexes and the subsequent
CC transcription of E2F target genes which are responsible for the
CC progression through the G(1) phase. Hypophosphorylates RB1 in early
CC G(1) phase. Cyclin D-CDK4 complexes are major integrators of various
CC mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a
CC cell-cycle-dependent manner and represses its transcriptional activity.
CC Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for
CC nuclear translocation and activity of the cyclin D-CDK4 complex (By
CC similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22;
CC Evidence={ECO:0000269|PubMed:1423597};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.22; Evidence={ECO:0000269|PubMed:1423597};
CC -!- ACTIVITY REGULATION: Both phosphorylation at Thr-172 and binding of a
CC D-type cyclin are necessary for enzymatic activity. Full activation of
CC the cyclin-D-CDK4 complex appears to require other factors such as
CC recruitment of the substrate via a substrate recruitment motif, and/or
CC formation of the CDKN1B ternary complex. Inhibited by INK4 family
CC members. In resting cells, the non-tyrosine-phosphorylated form of
CC CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in
CC proliferating cells, tyrosine phosphorylation of CDKN1B allows
CC phosphorylation of Thr-172 of CDK4 and subsequent activation.
CC {ECO:0000250|UniProtKB:P11802}.
CC -!- SUBUNIT: Component of the D-CDK4 complex, composed of CDK4 and some D-
CC type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the
CC complex with CCND1, CCND2 or CCND3. Interacts with ZNF655. Forms a
CC ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4
CC enzymatic activity. Interacts directly with CDKN1B (phosphorylated on
CC 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin
CC D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and
CC enhances the cyclin D-CDK4 complex activity. CDK4 activity is either
CC inhibited or enhanced depending on stoichiometry of complex. The non-
CC tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation
CC of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with
CC CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts
CC directly with CDKN1A (via its N-terminal); the interaction promotes the
CC assembly of the cyclin D-CDK4 complex, its nuclear translocation and
CC promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with
CC CCND1; the interaction is prevented with the binding of CCND1 to INSM1
CC during cell cycle progression (By similarity). Interacts with SEI1 and
CC CCND1. Probably forms a complex composed of chaperones HSP90 and HSP70,
CC co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT,
CC RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP
CC and PTGES3/p23 (By similarity). Interacts with CEBPA (when
CC phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (By
CC similarity). {ECO:0000250|UniProtKB:P11802,
CC ECO:0000269|PubMed:10580009, ECO:0000269|PubMed:15107404,
CC ECO:0000269|PubMed:19767775}.
CC -!- INTERACTION:
CC P30285; P25322: Ccnd1; NbExp=15; IntAct=EBI-847225, EBI-847243;
CC P30285; P46414: Cdkn1b; NbExp=2; IntAct=EBI-847225, EBI-1005742;
CC P30285; P24385: CCND1; Xeno; NbExp=2; IntAct=EBI-847225, EBI-375001;
CC P30285; P06400: RB1; Xeno; NbExp=2; IntAct=EBI-847225, EBI-491274;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11802}. Nucleus
CC {ECO:0000250|UniProtKB:P11802}. Nucleus membrane
CC {ECO:0000250|UniProtKB:P11802}. Note=Cytoplasmic when non-complexed.
CC Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress
CC through G(1) phase. The complex accumulates on the nuclear membrane and
CC enters the nucleus on transition from G(1) to S phase. Also present in
CC nucleoli and heterochromatin lumps. Colocalizes with RB1 after release
CC into the nucleus (By similarity). {ECO:0000250|UniProtKB:P11802}.
CC -!- PTM: Phosphorylation at Thr-172 is required for enzymatic activity.
CC Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo,
CC appears to be phosphorylated by a proline-directed kinase. In the
CC cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4
CC enzyme activity, is dependent on the tyrosine phosphorylation state of
CC CDKN1B. Thus, in proliferating cells, CDK4 within the complex is
CC phosphorylated on Thr-172 in the T-loop. In resting cells,
CC phosphorylation on Thr-172 is prevented by the non-tyrosine-
CC phosphorylated form of CDKN1B (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
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 AlphaFoldDB; P30285; -.
DR SMR; P30285; -.
DR BioGRID; 198645; 25.
DR ComplexPortal; CPX-2073; Cyclin D1-CDK4 complex.
DR ComplexPortal; CPX-2074; Cyclin D2-CDK4 complex.
DR ComplexPortal; CPX-2077; Cyclin D3-CDK4 complex.
DR CORUM; P30285; -.
DR DIP; DIP-194N; -.
DR IntAct; P30285; 17.
DR MINT; P30285; -.
DR STRING; 10090.ENSMUSP00000006911; -.
DR BindingDB; P30285; -.
DR ChEMBL; CHEMBL2134; -.
DR iPTMnet; P30285; -.
DR PhosphoSitePlus; P30285; -.
DR SwissPalm; P30285; -.
DR EPD; P30285; -.
DR jPOST; P30285; -.
DR PaxDb; P30285; -.
DR PeptideAtlas; P30285; -.
DR PRIDE; P30285; -.
DR ProteomicsDB; 281143; -.
DR Antibodypedia; 4190; 1123 antibodies from 47 providers.
DR DNASU; 12567; -.
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 VEuPathDB; HostDB:ENSMUSG00000006728; -.
DR eggNOG; KOG0594; Eukaryota.
DR GeneTree; ENSGT00940000154770; -.
DR InParanoid; P30285; -.
DR OMA; KNFPPLM; -.
DR OrthoDB; 1037602at2759; -.
DR PhylomeDB; P30285; -.
DR TreeFam; TF101022; -.
DR BRENDA; 2.7.11.22; 3474.
DR Reactome; R-MMU-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-MMU-2559585; Oncogene Induced Senescence.
DR Reactome; R-MMU-3214858; RMTs methylate histone arginines.
DR Reactome; R-MMU-69231; Cyclin D associated events in G1.
DR Reactome; R-MMU-75815; Ubiquitin-dependent degradation of Cyclin D.
DR Reactome; R-MMU-8849470; PTK6 Regulates Cell Cycle.
DR Reactome; R-MMU-8878166; Transcriptional regulation by RUNX2.
DR Reactome; R-MMU-9616222; Transcriptional regulation of granulopoiesis.
DR Reactome; R-MMU-9754119; Drug-mediated inhibition of CDK4/CDK6 activity.
DR BioGRID-ORCS; 12567; 12 hits in 76 CRISPR screens.
DR ChiTaRS; Cdk4; mouse.
DR PRO; PR:P30285; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P30285; protein.
DR Bgee; ENSMUSG00000006728; Expressed in metanephric ureteric bud and 284 other tissues.
DR ExpressionAtlas; P30285; baseline and differential.
DR Genevisible; P30285; MM.
DR GO; GO:0005923; C:bicellular tight junction; IDA:MGI.
DR GO; GO:0000785; C:chromatin; ISO:MGI.
DR GO; GO:0097128; C:cyclin D1-CDK4 complex; IPI:ComplexPortal.
DR GO; GO:0097129; C:cyclin D2-CDK4 complex; IDA:MGI.
DR GO; GO:0097130; C:cyclin D3-CDK4 complex; ISO:MGI.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016592; C:mediator complex; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; ISO:MGI.
DR GO; GO:0005730; C:nucleolus; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0030332; F:cyclin binding; IPI:MGI.
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:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IMP:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IBA:GO_Central.
DR GO; GO:0060612; P:adipose tissue development; IMP:MGI.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:MGI.
DR GO; GO:0071353; P:cellular response to interleukin-4; IDA:MGI.
DR GO; GO:1904637; P:cellular response to ionomycin; IDA:MGI.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:MGI.
DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IDA:MGI.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0045793; P:positive regulation of cell size; ISO:MGI.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:MGI.
DR GO; GO:0010468; P:regulation of gene expression; ISO:MGI.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IMP:MGI.
DR GO; GO:0046890; P:regulation of lipid biosynthetic process; IMP:MGI.
DR GO; GO:0050994; P:regulation of lipid catabolic process; IMP:MGI.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; IMP:MGI.
DR GO; GO:0010288; P:response to lead ion; ISO:MGI.
DR GO; GO:0010033; P:response to organic substance; ISO:MGI.
DR GO; GO:0033574; P:response to testosterone; ISO:MGI.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IDA:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
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; Cytoplasm; Kinase;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proto-oncogene;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P11802"
FT CHAIN 2..303
FT /note="Cyclin-dependent kinase 4"
FT /id="PRO_0000085779"
FT DOMAIN 6..295
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 50..56
FT /note="Required for binding D-type cyclins"
FT /evidence="ECO:0000250"
FT ACT_SITE 140
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 12..20
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 35
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P11802"
FT MOD_RES 172
FT /note="Phosphothreonine; by CAK"
FT /evidence="ECO:0000269|PubMed:8139570"
FT MOD_RES 300
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35426"
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
