P30285 (CDK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 136. 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. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression 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
|BioGrid||198645. 20 interactions.|
|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||184.108.40.206. 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|