P35426 (CDK4_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 4
EC=2.7.11.22

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

Gene names

Name:

Cdk4

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	303 AA.
Sequence status	Complete.
Protein existence	Evidence 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 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 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 expression pattern PubMed 11598123. Source: RGD organ regeneration Inferred from expression pattern PubMed 16534847. Source: RGD positive regulation of apoptotic process Inferred from mutant phenotype PubMed 18353414. Source: RGD positive regulation of cell cycle Traceable author statement PubMed 12163013. 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: Compara positive regulation of translation Inferred from mutant phenotype PubMed 12163013. Source: RGD response to drug Inferred from electronic annotation. Source: Compara 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 testosterone stimulus Inferred from direct assay PubMed 17962342. Source: RGD response to toxin Inferred from expression pattern PubMed 17343987. Source: RGD signal transduction Inferred from electronic annotation. Source: Compara
Cellular_component	chromatin Inferred from electronic annotation. Source: Compara cyclin-dependent protein kinase holoenzyme complex Inferred from electronic annotation. Source: Compara cytosol Inferred from electronic annotation. Source: Compara nuclear membrane Inferred from electronic annotation. Source: Compara nucleolus Inferred from electronic annotation. Source: Compara 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: Compara transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12163013. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 303	303	Cyclin-dependent kinase 4		PRO_0000085781
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 By similarity

Sequences

	Sequence		Length	Mass (Da)
	P35426 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 7E92F2A70B198423	FASTA	303	33,799
	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

References

	« Hide 'large scale' referencesShow '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.
IPI	IPI00198608.
PIR	JN0460.
RefSeq	NP_446045.1. NM_053593.2.
UniGene	Rn.6115.
3D structure databases
ProteinModelPortal	P35426.
SMR	P35426. Positions 2-299.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000034754.
Proteomic databases
PRIDE	P35426.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000031796; ENSRNOP00000034754; ENSRNOG00000025602.
GeneID	94201.
KEGG	rno:94201.
Organism-specific databases
CTD	1019.
RGD	621120. Cdk4.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101791.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	P35426.
KO	K02089.
OrthoDB	EOG4NGGN6.
Enzyme and pathway databases
BRENDA	2.7.11.22. 5301.
Gene expression databases
ArrayExpress	P35426.
Genevestigator	P35426.
GermOnline	ENSRNOG00000025602. Rattus norvegicus.
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
NextBio	617871.

Entry information

Entry name

CDK4_RAT

Accession

Primary (citable) accession number: P35426

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program