P30285 (CDK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 4
EC=2.7.11.22

Alternative name(s):
CRK3
Cell division protein kinase 4
PSK-J3

Gene names

Name:	Cdk4
Synonyms:	Crk3

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	303 AA.
Sequence status	Complete.
Protein existence	Evidence at protein 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. Ref.1
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 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
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.
Post-translational modification	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
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 process	Cell cycle Cell division
Cellular component	Cytoplasm Membrane Nucleus
Disease	Proto-oncogene
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1/S transition of mitotic cell cycle Inferred from electronic annotation. Source: Compara cell division Inferred from electronic annotation. Source: UniProtKB-KW circadian rhythm Inferred from electronic annotation. Source: Compara organ regeneration Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of cell size Inferred from electronic annotation. Source: Compara positive regulation of fibroblast proliferation Inferred from electronic annotation. Source: Compara positive regulation of translation Inferred from electronic annotation. Source: Compara regulation of cell cycle Inferred from direct assay PubMed 12588994. Source: MGI regulation of cell proliferation Inferred from mutant phenotype PubMed 12917627. Source: MGI response to drug Inferred from electronic annotation. Source: Compara response to hyperoxia Inferred from electronic annotation. Source: Compara response to lead ion Inferred from electronic annotation. Source: Compara response to testosterone stimulus Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara signal transduction Inferred from direct assay PubMed 12130539. Source: MGI
Cellular_component	chromatin Inferred from electronic annotation. Source: Compara cyclin-dependent protein kinase holoenzyme complex Inferred from physical interaction PubMed 12970760. Source: MGI cytosol Inferred from electronic annotation. Source: Compara nuclear membrane Inferred from electronic annotation. Source: Compara nucleolus Inferred from electronic annotation. Source: Compara perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara transcription factor complex Inferred from direct assay PubMed 10082561. Source: MGI
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12970171PubMed 12970760. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ccnd1	P25322	9	EBI-847225,EBI-847243
RB1	P06400	2	EBI-847225,EBI-491274	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 303	303	Cyclin-dependent kinase 4		PRO_0000085779
Regions
	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
Sites
	Active site	140	1	Proton acceptor By similarity
	Binding site	35	1	ATP By similarity
Amino acid modifications
	Modified residue	172	1	Phosphothreonine; by CAK Ref.5

Sequences

	Sequence		Length	Mass (Da)
	P30285 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: CB4F42A8AA13634A	FASTA	303	33,751
	10 20 30 40 50 60 MAATRYEPVA 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 EVSLPRGAFA PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKEES DAE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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.
[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]. Strain: C57BL/6. Tissue: Olfactory epithelium.
[3]	"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. Strain: C57BL/6. Tissue: Embryonic brain.
[4]	"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. Strain: CBA. Tissue: Bone marrow.
[5]	"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.
[6]	"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.
[7]	"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.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00128326.
PIR	A44293.
RefSeq	NP_034000.1. NM_009870.3.
UniGene	Mm.6839.
3D structure databases
ProteinModelPortal	P30285.
SMR	P30285. Positions 5-295.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-194N.
IntAct	P30285. 10 interactions.
MINT	MINT-4090398.
PTM databases
PhosphoSite	P30285.
Proteomic databases
PaxDb	P30285.
PRIDE	P30285.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000006911; ENSMUSP00000006911; ENSMUSG00000006728.
GeneID	12567.
KEGG	mmu:12567.
Organism-specific databases
CTD	1019.
MGI	MGI:88357. Cdk4.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	P30285.
KO	K02089.
OMA	ARIYSCH.
OrthoDB	EOG4NGGN6.
Enzyme and pathway databases
BRENDA	2.7.11.22. 3474.
Reactome	REACT_118161. Cell Cycle. REACT_120463. Meiosis. REACT_27235. Meiotic Recombination (mouse).
Gene expression databases
ArrayExpress	P30285.
Bgee	P30285.
CleanEx	MM_CDK4.
Genevestigator	P30285.
GermOnline	ENSMUSG00000006728. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P30285.
ChEMBL	CHEMBL2134.
NextBio	281662.
SOURCE	Search...

Entry information

Entry name

CDK4_MOUSE

Accession

Primary (citable) accession number: P30285

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program