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P35426

- CDK4_RAT

UniProt

P35426 - CDK4_RAT

Protein

Cyclin-dependent kinase 4

Gene

Cdk4

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 122 (01 Oct 2014)
      Sequence version 1 (01 Jun 1994)
      Previous versions | rss
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    Functioni

    Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Enzyme regulationi

    Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequennt activation.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei35 – 351ATPPROSITE-ProRule annotation
    Active sitei140 – 1401Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi12 – 209ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. cyclin binding Source: RGD
    3. cyclin-dependent protein serine/threonine kinase activity Source: RGD
    4. protein complex binding Source: RGD

    GO - Biological processi

    1. cell division Source: UniProtKB-KW
    2. circadian rhythm Source: RGD
    3. G1/S transition of mitotic cell cycle Source: Ensembl
    4. lens development in camera-type eye Source: RGD
    5. negative regulation of cell cycle arrest Source: UniProtKB
    6. organ regeneration Source: RGD
    7. positive regulation of apoptotic process Source: RGD
    8. positive regulation of cell proliferation Source: RGD
    9. positive regulation of cell size Source: RGD
    10. positive regulation of fibroblast proliferation Source: Ensembl
    11. positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
    12. positive regulation of translation Source: RGD
    13. response to drug Source: Ensembl
    14. response to hyperoxia Source: RGD
    15. response to lead ion Source: RGD
    16. response to organic substance Source: RGD
    17. response to testosterone Source: RGD
    18. response to toxic substance Source: RGD
    19. signal transduction Source: Ensembl

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Cell cycle, Cell division

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.22. 5301.
    ReactomeiREACT_194748. Senescence-Associated Secretory Phenotype (SASP).
    REACT_196261. Meiotic recombination.
    REACT_203770. Oxidative Stress Induced Senescence.
    REACT_215142. Oncogene Induced Senescence.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cyclin-dependent kinase 4 (EC:2.7.11.22)
    Alternative name(s):
    Cell division protein kinase 4
    PSK-J3
    Gene namesi
    Name:Cdk4
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 7

    Organism-specific databases

    RGDi621120. Cdk4.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity. Membrane By similarity
    Note: Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress through G1 phase. The complex accumulates on the nuclear membrane and enters the nucleus on transition from G1 to S phase. Also present in nucleoli and heterochromatin lumps. Colocalizes with RB1 after release into the nucleus By similarity.By similarity

    GO - Cellular componenti

    1. chromatin Source: Ensembl
    2. cyclin-dependent protein kinase holoenzyme complex Source: Ensembl
    3. cytosol Source: Ensembl
    4. nuclear membrane Source: Ensembl
    5. nucleolus Source: Ensembl
    6. nucleus Source: RGD
    7. perinuclear region of cytoplasm Source: RGD
    8. tight junction Source: Ensembl
    9. transcription factor complex Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Keywords - Diseasei

    Proto-oncogene

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 303302Cyclin-dependent kinase 4PRO_0000085781Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanineBy similarity
    Modified residuei172 – 1721Phosphothreonine; by CAKBy similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    PRIDEiP35426.

    Expressioni

    Tissue specificityi

    Expressed in fetal and adult lung. Also expressed in brain, heart, liver, skeletal muscle and testes.1 Publication

    Developmental stagei

    In developing lung, high expression at day 17 after which levels decline to barely detectable levels at birth. Levels then increase postnataly until postnatal day 6 and decline in adulthood. Preferentially expressed in proliferating cells.1 Publication

    Gene expression databases

    ArrayExpressiP35426.
    GenevestigatoriP35426.

    Interactioni

    Subunit structurei

    Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression By similarity.By similarity

    Protein-protein interaction databases

    BioGridi250181. 4 interactions.
    STRINGi10116.ENSRNOP00000034754.

    Structurei

    3D structure databases

    ProteinModelPortaliP35426.
    SMRiP35426. Positions 2-299.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini6 – 295290Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni50 – 567Required for binding D-type cyclinsBy similarity

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00720000108415.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiP35426.
    KOiK02089.
    OMAiIDQDLRT.
    OrthoDBiEOG73JKVV.
    PhylomeDBiP35426.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P35426-1 [UniParc]FASTAAdd to Basket

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    MATTRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP    50
    VSTVREVALL RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL 100
    RTYLDKAPPP GLPVETIKDL MRQFLSGLDF LHANCIVHRD LKPENILVTS 150
    NGTVKLADFG LARIYSYQMA LTPVVVTLWY RAPEVLLQST YATPVDMWSV 200
    GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR EVSLPRGAFS 250
    PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP LKRISAFRAL QHSYLHKEES 300
    DPE 303
    Length:303
    Mass (Da):33,799
    Last modified:June 1, 1994 - v1
    Checksum:i7E92F2A70B198423
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L11007 mRNA. Translation: AAA40903.1.
    BC070956 mRNA. Translation: AAH70956.1.
    PIRiJN0460.
    RefSeqiNP_446045.1. NM_053593.2.
    UniGeneiRn.6115.

    Genome annotation databases

    EnsembliENSRNOT00000031796; ENSRNOP00000034754; ENSRNOG00000025602.
    GeneIDi94201.
    KEGGirno:94201.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L11007 mRNA. Translation: AAA40903.1 .
    BC070956 mRNA. Translation: AAH70956.1 .
    PIRi JN0460.
    RefSeqi NP_446045.1. NM_053593.2.
    UniGenei Rn.6115.

    3D structure databases

    ProteinModelPortali P35426.
    SMRi P35426. Positions 2-299.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 250181. 4 interactions.
    STRINGi 10116.ENSRNOP00000034754.

    Proteomic databases

    PRIDEi P35426.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000031796 ; ENSRNOP00000034754 ; ENSRNOG00000025602 .
    GeneIDi 94201.
    KEGGi rno:94201.

    Organism-specific databases

    CTDi 1019.
    RGDi 621120. Cdk4.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00720000108415.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi P35426.
    KOi K02089.
    OMAi IDQDLRT.
    OrthoDBi EOG73JKVV.
    PhylomeDBi P35426.

    Enzyme and pathway databases

    BRENDAi 2.7.11.22. 5301.
    Reactomei REACT_194748. Senescence-Associated Secretory Phenotype (SASP).
    REACT_196261. Meiotic recombination.
    REACT_203770. Oxidative Stress Induced Senescence.
    REACT_215142. Oncogene Induced Senescence.

    Miscellaneous databases

    NextBioi 617871.
    PROi P35426.

    Gene expression databases

    ArrayExpressi P35426.
    Genevestigatori P35426.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Cloning of the rat cyclin-dependent kinase 4 cDNA: implication in proliferation-dependent expression in rat tissues."
      Cho F.S., Phillips K.S., Khan S.A., Weaver T.E.
      Biochem. Biophys. Res. Commun. 191:860-865(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
      Tissue: Fetal lung.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Heart.

    Entry informationi

    Entry nameiCDK4_RAT
    AccessioniPrimary (citable) accession number: P35426
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 1, 1994
    Last sequence update: June 1, 1994
    Last modified: October 1, 2014
    This is version 122 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3