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P35426

- CDK4_RAT

UniProt

P35426 - CDK4_RAT

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Protein
Cyclin-dependent kinase 4
Gene
Cdk4
Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at transcript leveli

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.

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 – 351ATP By similarity
Active sitei140 – 1401Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi12 – 209ATP By similarity

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
Complete GO annotation...

GO - Biological processi

  1. G1/S transition of mitotic cell cycle Source: Ensembl
  2. cell division Source: UniProtKB-KW
  3. circadian rhythm Source: RGD
  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 G2/M transition of mitotic cell cycle Source: UniProtKB
  8. positive regulation of apoptotic process Source: RGD
  9. positive regulation of cell proliferation Source: RGD
  10. positive regulation of cell size Source: RGD
  11. positive regulation of fibroblast proliferation Source: Ensembl
  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
Complete GO annotation...

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.

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
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

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

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine By similarity
Modified residuei172 – 1721Phosphothreonine; by CAK By 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.

Protein-protein interaction databases

BioGridi250181. 4 interactions.
STRINGi10116.ENSRNOP00000034754.

Structurei

3D structure databases

ProteinModelPortaliP35426.
SMRiP35426. Positions 2-299.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini6 – 295290Protein kinase
Add
BLAST

Region

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

Sequence similaritiesi

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

« Hide

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...

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

« Hide 'large scale' publications
  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: September 3, 2014
This is version 121 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

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