CDK4_BOVIN
ID CDK4_BOVIN Reviewed; 303 AA.
AC Q32KY4;
DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-DEC-2005, sequence version 1.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=Cyclin-dependent kinase 4;
DE EC=2.7.11.22;
DE AltName: Full=Cell division protein kinase 4;
GN Name=CDK4;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Liver;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
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 -!- 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}.
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DR EMBL; BC109858; AAI09859.1; -; mRNA.
DR RefSeq; NP_001032683.1; NM_001037594.2.
DR RefSeq; XP_005206610.1; XM_005206553.3.
DR AlphaFoldDB; Q32KY4; -.
DR SMR; Q32KY4; -.
DR BioGRID; 167251; 1.
DR STRING; 9913.ENSBTAP00000009420; -.
DR PaxDb; Q32KY4; -.
DR PRIDE; Q32KY4; -.
DR Ensembl; ENSBTAT00000009420; ENSBTAP00000009420; ENSBTAG00000007160.
DR Ensembl; ENSBTAT00000079975; ENSBTAP00000071543; ENSBTAG00000007160.
DR GeneID; 510618; -.
DR KEGG; bta:510618; -.
DR CTD; 1019; -.
DR VEuPathDB; HostDB:ENSBTAG00000007160; -.
DR eggNOG; KOG0594; Eukaryota.
DR GeneTree; ENSGT00940000154770; -.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; Q32KY4; -.
DR OMA; KNFPPLM; -.
DR OrthoDB; 988547at2759; -.
DR TreeFam; TF101022; -.
DR Reactome; R-BTA-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-BTA-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-BTA-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-BTA-2559585; Oncogene Induced Senescence.
DR Reactome; R-BTA-69231; Cyclin D associated events in G1.
DR Reactome; R-BTA-75815; Ubiquitin-dependent degradation of Cyclin D.
DR Reactome; R-BTA-8849470; PTK6 Regulates Cell Cycle.
DR Reactome; R-BTA-8878166; Transcriptional regulation by RUNX2.
DR Reactome; R-BTA-9754119; Drug-mediated inhibition of CDK4/CDK6 activity.
DR Proteomes; UP000009136; Chromosome 5.
DR Bgee; ENSBTAG00000007160; Expressed in uterine cervix and 106 other tissues.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
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; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IBA:GO_Central.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
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 2: Evidence at transcript 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_0000282334"
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"
SQ SEQUENCE 303 AA; 33647 MW; 3623FDD0B25EF20A CRC64;
MATSRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGGAGGGLP ISTVREVALL
RRLEAFEHPN VVRLMDVCAT ARTDRETKVT LVFEHVDQDL RTYLDKAPPP GLPVETIKDL
MRQFLRGLDF LHANCIVHRD LKPENILVTS GGTVKLADFG LARIYSYQMA LTPVVVTLWY
RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR
DVSLPRGAFS PRGPRPVQSV VPELEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKAEG
DAE
