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P35426 (CDK4_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 120. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase 4

EC=2.7.11.22
Alternative name(s):
Cell division protein kinase 4
PSK-J3
Gene names
Name:Cdk4
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length303 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

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 activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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.

Subunit structure

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.

Subcellular location

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.

Tissue specificity

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

Developmental stage

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. Ref.1

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Cell division
   Cellular componentCytoplasm
Membrane
Nucleus
   DiseaseProto-oncogene
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG1/S transition of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

cell division

Inferred from electronic annotation. Source: UniProtKB-KW

circadian rhythm

Inferred from expression pattern PubMed 11598123. Source: RGD

lens development in camera-type eye

Inferred from expression pattern PubMed 10620399. Source: RGD

negative regulation of cell cycle arrest

Inferred from sequence or structural similarity. Source: UniProtKB

organ regeneration

Inferred from expression pattern PubMed 16534847. Source: RGD

positive regulation of G2/M transition of mitotic cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of apoptotic process

Inferred from mutant phenotype PubMed 18353414. Source: RGD

positive regulation of cell proliferation

Inferred from mutant phenotype PubMed 17635516. Source: RGD

positive regulation of cell size

Inferred from mutant phenotype PubMed 12163013. Source: RGD

positive regulation of fibroblast proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of translation

Inferred from mutant phenotype PubMed 12163013. Source: RGD

response to drug

Inferred from electronic annotation. Source: Ensembl

response to hyperoxia

Inferred from expression pattern PubMed 18082050. Source: RGD

response to lead ion

Inferred from mutant phenotype PubMed 18353414. Source: RGD

response to organic substance

Inferred from mutant phenotype PubMed 18353414. Source: RGD

response to testosterone

Inferred from direct assay PubMed 17962342. Source: RGD

response to toxic substance

Inferred from expression pattern PubMed 17343987. Source: RGD

signal transduction

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentchromatin

Inferred from electronic annotation. Source: Ensembl

cyclin-dependent protein kinase holoenzyme complex

Inferred from electronic annotation. Source: Ensembl

cytosol

Inferred from electronic annotation. Source: Ensembl

nuclear membrane

Inferred from electronic annotation. Source: Ensembl

nucleolus

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay PubMed 7585545. Source: RGD

perinuclear region of cytoplasm

Inferred from direct assay PubMed 15161838. Source: RGD

tight junction

Inferred from electronic annotation. Source: Ensembl

transcription factor complex

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cyclin binding

Inferred from physical interaction PubMed 15809057. Source: RGD

cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 12163013. Source: RGD

protein complex binding

Inferred from physical interaction PubMed 8651753. Source: RGD

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 303302Cyclin-dependent kinase 4
PRO_0000085781

Regions

Domain6 – 295290Protein kinase
Nucleotide binding12 – 209ATP By similarity
Region50 – 567Required for binding D-type cyclins By similarity

Sites

Active site1401Proton acceptor By similarity
Binding site351ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue1721Phosphothreonine; by CAK By similarity

Sequences

Sequence LengthMass (Da)Tools
P35426 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 7E92F2A70B198423

FASTA30333,799
        10         20         30         40         50         60 
MATTRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP VSTVREVALL 

        70         80         90        100        110        120 
RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL RTYLDKAPPP GLPVETIKDL 

       130        140        150        160        170        180 
MRQFLSGLDF LHANCIVHRD LKPENILVTS NGTVKLADFG LARIYSYQMA LTPVVVTLWY 

       190        200        210        220        230        240 
RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR 

       250        260        270        280        290        300 
EVSLPRGAFS PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP LKRISAFRAL QHSYLHKEES 


DPE 

« Hide

References

« Hide 'large scale' references
[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L11007 mRNA. Translation: AAA40903.1.
BC070956 mRNA. Translation: AAH70956.1.
PIRJN0460.
RefSeqNP_446045.1. NM_053593.2.
UniGeneRn.6115.

3D structure databases

ProteinModelPortalP35426.
SMRP35426. Positions 2-299.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid250181. 4 interactions.
STRING10116.ENSRNOP00000034754.

Proteomic databases

PRIDEP35426.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000031796; ENSRNOP00000034754; ENSRNOG00000025602.
GeneID94201.
KEGGrno:94201.

Organism-specific databases

CTD1019.
RGD621120. Cdk4.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00720000108415.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP35426.
KOK02089.
OMAIDQDLRT.
OrthoDBEOG73JKVV.
PhylomeDBP35426.

Enzyme and pathway databases

BRENDA2.7.11.22. 5301.

Gene expression databases

ArrayExpressP35426.
GenevestigatorP35426.

Family and domain databases

InterProIPR011009. 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]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio617871.
PROP35426.

Entry information

Entry nameCDK4_RAT
AccessionPrimary (citable) accession number: P35426
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: June 11, 2014
This is version 120 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families