P35426 (CDK4_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 118. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase 4
Cell division protein kinase 4
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||303 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at transcript level|
General annotation (Comments)
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.
ATP + a protein = ADP + a phosphoprotein.
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.
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.
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.
Expressed in fetal and adult lung. Also expressed in brain, heart, liver, skeletal muscle and testes. Ref.1
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
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 303||302||Cyclin-dependent kinase 4||PRO_0000085781|
|Domain||6 – 295||290||Protein kinase|
|Nucleotide binding||12 – 20||9||ATP By similarity|
|Region||50 – 56||7||Required for binding D-type cyclins By similarity|
|Active site||140||1||Proton acceptor By similarity|
|Binding site||35||1||ATP By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylalanine By similarity|
|Modified residue||172||1||Phosphothreonine; by CAK By similarity|
|||"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.
|||"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].
|+||Additional computationally mapped references.|
|L11007 mRNA. Translation: AAA40903.1.|
BC070956 mRNA. Translation: AAH70956.1.
|RefSeq||NP_446045.1. NM_053593.2. |
3D structure databases
|SMR||P35426. Positions 2-299. |
Protein-protein interaction databases
|BioGrid||250181. 4 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000031796; ENSRNOP00000034754; ENSRNOG00000025602. |
|RGD||621120. Cdk4. |
Enzyme and pathway databases
|BRENDA||184.108.40.206. 5301. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: P35426|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families