P30285 (CDK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 133. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase 4
Cell division protein kinase 4
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||303 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein 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. Ref.1
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 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 By similarity. Interacts with SEI1 and CCND1. Ref.6 Ref.7
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.
Phosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T-loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B By similarity. Ref.5
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_0000085779|
|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 Ref.5|
|||"Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins."|
Matsushime H., Ewen M.E., Strom D.K., Kato J.Y., Hanks S.K., Roussel M.F., Sherr C.J.
Cell 71:323-334(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY.
|||"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: Olfactory epithelium.
|||"An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain."|
Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A., Wilkinson D.G., Charnay P.
Oncogene 7:2499-2506(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 142-188.
Tissue: Embryonic brain.
|||"Novel CDC2-related protein kinases produced in murine hematopoietic stem cells."|
Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V.
Gene 124:305-306(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 144-178.
Tissue: Bone marrow.
|||"Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase."|
Kato J.-Y., Matsuoka M., Strom D.K., Sherr C.J.
Mol. Cell. Biol. 14:2713-2721(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-172.
|||"Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)."|
Sugimoto M., Nakamura T., Ohtani N., Hampson L., Hampson I.N., Shimamoto A., Furuichi Y., Okumura K., Niwa S., Taya Y., Hara E.
Genes Dev. 13:3027-3033(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SEI1.
|||"Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation."|
Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.
Oncogene 28:4317-4325(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CCND1.
|+||Additional computationally mapped references.|
|L01640 mRNA. Translation: AAA37646.1.|
BC046336 mRNA. Translation: AAH46336.1.
BC052694 mRNA. Translation: AAH52694.1.
X57238 mRNA. Translation: CAA40514.1.
X65069 mRNA. Translation: CAA46202.1.
|RefSeq||NP_034000.1. NM_009870.3. |
3D structure databases
|SMR||P30285. Positions 5-295. |
Protein-protein interaction databases
|IntAct||P30285. 12 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728. |
|UCSC||uc007hhv.2. mouse. |
|MGI||MGI:88357. Cdk4. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 3474. |
|Reactome||REACT_118161. Cell Cycle. |
REACT_27235. Meiotic Recombination.
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: P30285|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|