CDK4_RAT
ID CDK4_RAT Reviewed; 303 AA.
AC P35426;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Cyclin-dependent kinase 4;
DE EC=2.7.11.22;
DE AltName: Full=Cell division protein kinase 4;
DE AltName: Full=PSK-J3;
GN Name=Cdk4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Fetal lung;
RX PubMed=8466525; DOI=10.1006/bbrc.1993.1296;
RA Cho F.S., Phillips K.S., Khan S.A., Weaver T.E.;
RT "Cloning of the rat cyclin-dependent kinase 4 cDNA: implication in
RT proliferation-dependent expression in rat tissues.";
RL Biochem. Biophys. Res. Commun. 191:860-865(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-300, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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|UniProtKB:P11802}.
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 -!- 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;
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 SEI1 and ZNF655.
CC Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating
CC CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated
CC on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the
CC cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation
CC and enhances the cyclin D-CDK4 complex activity. CDK4 activity is
CC either inhibited or enhanced depending on stoichiometry of complex. The
CC non-tyrosine-phosphorylated form of CDKN1B prevents T-loop
CC phosphorylation of CDK4 producing inactive CDK4. Interacts
CC (unphosphorylated form) with CDK2. Also forms ternary complexes with
CC CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal);
CC the interaction promotes the assembly of the cyclin D-CDK4 complex, its
CC nuclear translocation and promotes the cyclin D-dependent enzyme
CC activity of CDK4. Interacts with CCND1; the interaction is prevented
CC with the binding of CCND1 to INSM1 during cell cycle progression.
CC Probably forms a complex composed of chaperones HSP90 and HSP70, co-
CC chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1
CC and NR3C1; this complex does not contain co-chaperones STIP1/HOP and
CC PTGES3/p23. Interacts with CEBPA (when phosphorylated). Interacts with
CC FNIP1 and FNIP2. {ECO:0000250|UniProtKB:P11802,
CC ECO:0000250|UniProtKB:P30285}.
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 -!- TISSUE SPECIFICITY: Expressed in fetal and adult lung. Also expressed
CC in brain, heart, liver, skeletal muscle and testes.
CC {ECO:0000269|PubMed:8466525}.
CC -!- DEVELOPMENTAL STAGE: In developing lung, high expression at day 17
CC after which levels decline to barely detectable levels at birth. Levels
CC then increase postnatally until postnatal day 6 and decline in
CC adulthood. Preferentially expressed in proliferating cells.
CC {ECO:0000269|PubMed:8466525}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
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DR EMBL; L11007; AAA40903.1; -; mRNA.
DR EMBL; BC070956; AAH70956.1; -; mRNA.
DR PIR; JN0460; JN0460.
DR RefSeq; NP_446045.1; NM_053593.2.
DR AlphaFoldDB; P35426; -.
DR SMR; P35426; -.
DR BioGRID; 250181; 4.
DR ComplexPortal; CPX-2075; Cyclin D1-CDK4 complex.
DR ComplexPortal; CPX-2076; Cyclin D2-CDK4 complex.
DR ComplexPortal; CPX-2078; Cyclin D3-CDK4 complex.
DR STRING; 10116.ENSRNOP00000034754; -.
DR iPTMnet; P35426; -.
DR PhosphoSitePlus; P35426; -.
DR jPOST; P35426; -.
DR PaxDb; P35426; -.
DR PRIDE; P35426; -.
DR GeneID; 94201; -.
DR KEGG; rno:94201; -.
DR CTD; 1019; -.
DR RGD; 621120; Cdk4.
DR VEuPathDB; HostDB:ENSRNOG00000025602; -.
DR eggNOG; KOG0594; Eukaryota.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; P35426; -.
DR OMA; KNFPPLM; -.
DR OrthoDB; 988547at2759; -.
DR PhylomeDB; P35426; -.
DR BRENDA; 2.7.11.22; 5301.
DR Reactome; R-RNO-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-RNO-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-RNO-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-RNO-2559585; Oncogene Induced Senescence.
DR Reactome; R-RNO-3214858; RMTs methylate histone arginines.
DR Reactome; R-RNO-69231; Cyclin D associated events in G1.
DR Reactome; R-RNO-75815; Ubiquitin-dependent degradation of Cyclin D.
DR Reactome; R-RNO-8849470; PTK6 Regulates Cell Cycle.
DR Reactome; R-RNO-9616222; Transcriptional regulation of granulopoiesis.
DR Reactome; R-RNO-9754119; Drug-mediated inhibition of CDK4/CDK6 activity.
DR PRO; PR:P35426; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000025602; Expressed in thymus and 19 other tissues.
DR Genevisible; P35426; RN.
DR GO; GO:0005923; C:bicellular tight junction; ISO:RGD.
DR GO; GO:0000785; C:chromatin; ISO:RGD.
DR GO; GO:0097128; C:cyclin D1-CDK4 complex; ISO:RGD.
DR GO; GO:0097129; C:cyclin D2-CDK4 complex; ISO:RGD.
DR GO; GO:0097130; C:cyclin D3-CDK4 complex; ISO:RGD.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0016592; C:mediator complex; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0030332; F:cyclin binding; IPI:RGD.
DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:RGD.
DR GO; GO:0016301; F:kinase activity; ISO:RGD.
DR GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
DR GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IBA:GO_Central.
DR GO; GO:0060612; P:adipose tissue development; ISO:RGD.
DR GO; GO:0031100; P:animal organ regeneration; IEP:RGD.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD.
DR GO; GO:0071353; P:cellular response to interleukin-4; ISO:RGD.
DR GO; GO:1904637; P:cellular response to ionomycin; ISO:RGD.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:RGD.
DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; ISO:RGD.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0002088; P:lens development in camera-type eye; IEP:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0045793; P:positive regulation of cell size; IMP:RGD.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; ISO:RGD.
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; IMP:RGD.
DR GO; GO:0006468; P:protein phosphorylation; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; ISO:RGD.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; ISO:RGD.
DR GO; GO:0046890; P:regulation of lipid biosynthetic process; ISO:RGD.
DR GO; GO:0050994; P:regulation of lipid catabolic process; ISO:RGD.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0055093; P:response to hyperoxia; IEP:RGD.
DR GO; GO:0010288; P:response to lead ion; IMP:RGD.
DR GO; GO:0010033; P:response to organic substance; IMP:RGD.
DR GO; GO:0033574; P:response to testosterone; IDA:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0007165; P:signal transduction; ISO:RGD.
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_0000085781"
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:0000250|UniProtKB:P30285"
FT MOD_RES 300
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
SQ SEQUENCE 303 AA; 33799 MW; 7E92F2A70B198423 CRC64;
MATTRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP VSTVREVALL
RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL RTYLDKAPPP GLPVETIKDL
MRQFLSGLDF LHANCIVHRD LKPENILVTS NGTVKLADFG LARIYSYQMA LTPVVVTLWY
RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR
EVSLPRGAFS PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP LKRISAFRAL QHSYLHKEES
DPE
