ID   CDK4_SHEEP              Reviewed;         303 AA.
AC   B2MVY4; B2CL06;
DT   08-MAR-2011, integrated into UniProtKB/Swiss-Prot.
DT   10-JUN-2008, sequence version 1.
DT   08-NOV-2023, entry version 66.
DE   RecName: Full=Cyclin-dependent kinase 4;
DE            EC=2.7.11.22;
DE   AltName: Full=Cell division protein kinase 4;
OS   Ovis aries (Sheep).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Caprinae; Ovis.
OX   NCBI_TaxID=9940;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Deng W.;
RT   "Molecular clone and sequence analysis of CDK4 from black-boned sheep (Ovis
RT   aries).";
RL   Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Liu G.Y., Ge C.R.;
RT   "CDK4 cyclin-dependent kinase 4.";
RL   Submitted (APR-2009) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 39-281.
RA   Rozance P.J., LoTurco D.G.;
RL   Submitted (FEB-2008) 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 a substrate for SMAD3,
CC       phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing
CC       its transcriptional activity. Component of the ternary complex, cyclin
CC       D/CDK4/CDKN1B, required for nuclear translocation and activity of the
CC       cyclin D-CDK4 complex (By 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   -!- 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 subsequennt activation.
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 FNIP1 and FNIP2.
CC       {ECO:0000250|UniProtKB:P11802, 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   -!- 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; EU626223; ACC93618.1; -; mRNA.
DR   EMBL; FJ943997; ACR46652.1; -; mRNA.
DR   EMBL; EU525168; ACB20722.1; -; mRNA.
DR   RefSeq; NP_001120741.1; NM_001127269.1.
DR   RefSeq; XP_012013938.1; XM_012158548.2.
DR   AlphaFoldDB; B2MVY4; -.
DR   SMR; B2MVY4; -.
DR   STRING; 9940.ENSOARP00000005709; -.
DR   PaxDb; 9940-ENSOARP00000005709; -.
DR   Ensembl; ENSOART00020000176; ENSOARP00020000114; ENSOARG00020000149.
DR   GeneID; 100144756; -.
DR   KEGG; oas:100144756; -.
DR   CTD; 1019; -.
DR   eggNOG; KOG0594; Eukaryota.
DR   OrthoDB; 244018at2759; -.
DR   Proteomes; UP000002356; Unplaced.
DR   GO; GO:0005923; C:bicellular tight junction; IEA:Ensembl.
DR   GO; GO:0000785; C:chromatin; IEA:Ensembl.
DR   GO; GO:0097128; C:cyclin D1-CDK4 complex; IEA:Ensembl.
DR   GO; GO:0097129; C:cyclin D2-CDK4 complex; IEA:Ensembl.
DR   GO; GO:0097130; C:cyclin D3-CDK4 complex; IEA:Ensembl.
DR   GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR   GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005730; C:nucleolus; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0005667; C:transcription regulator complex; IEA:Ensembl.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0030332; F:cyclin binding; IEA:Ensembl.
DR   GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IEA:UniProtKB-EC.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR   GO; GO:1904637; P:cellular response to ionomycin; IEA:Ensembl.
DR   GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IEA:Ensembl.
DR   GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IEA:Ensembl.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
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; IEA:Ensembl.
DR   GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR   GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; IEA:Ensembl.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; IEA:Ensembl.
DR   CDD; cd07863; STKc_CDK4; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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   PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1.
DR   PANTHER; PTHR24056:SF129; CYCLIN-DEPENDENT KINASE 4; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 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_0000405926"
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
//