Q64261 (CDK6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 6
EC=2.7.11.22

Alternative name(s):
CR2 protein kinase
Short name=CRK2
Cell division protein kinase 6
Serine/threonine-protein kinase PLSTIRE

Gene names

Name:	Cdk6
Synonyms:	Cdkn6, Crk2

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	326 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. Ref.6 Ref.7 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Activated by Thr-177 phosphorylation and Tyr-24 dephosphorylation By similarity. Rapidly down-regulated prior to cell differentiation (e.g. erythroid and osteoblast) By similarity.
Subunit structure	Interaction with D-type G1 cyclins. Cyclin binding promotes enzyme activation by phosphorylation at Thr-177 By similarity. Binds to RUNX1, CDKN2D, FBXO7 and CDKN2C/p18-INK4c. Forms a cytoplasmic complex with Hsp90/HSP90AB1 and CDC37. FBXO7-binding promotes D-type cyclin binding By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Cell projection › ruffle By similarity. Note: Localized to the ruffling edge of spreading fibroblasts. Kinase activity only in nucleus By similarity.
Tissue specificity	Expressed in subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles whose neural precursor cells (NPC) give rise to dentate granule neurons and olfactory bulb (OB) interneurons, respectively. Ref.8
Post-translational modification	Thr-177 phosphorylation and Tyr-24 dephosphorylation promotes kinase activity By similarity.
Disruption phenotype	Slight anemia and defective proliferation of some hematopoietic cells, thymocytes and progenitor cells. Females are reduced in size and often sterile. Prevents the expansion of neuronally committed precursors by prematurely exiting the cell cycle and lengthening G1 phase duration, reducing concomitantly the production of newborn neurons. Ref.5 Ref.7 Ref.8
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 Differentiation
Cellular component	Cell projection Cytoplasm Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Inferred from electronic annotation. Source: Compara Notch signaling pathway Inferred from direct assay Ref.7. Source: MGI T cell differentiation in thymus Inferred from mutant phenotype Ref.7. Source: MGI cell dedifferentiation Inferred from electronic annotation. Source: Compara cell division Inferred from electronic annotation. Source: UniProtKB-KW gliogenesis Inferred from electronic annotation. Source: Compara hematopoietic progenitor cell differentiation Inferred from mutant phenotype Ref.7. Source: MGI hematopoietic stem cell differentiation Inferred from mutant phenotype Ref.7. Source: MGI negative regulation of cell cycle Inferred from electronic annotation. Source: Compara negative regulation of cellular senescence Inferred from electronic annotation. Source: Compara negative regulation of epithelial cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of myeloid cell differentiation Inferred from electronic annotation. Source: Compara negative regulation of osteoblast differentiation Inferred from electronic annotation. Source: Compara positive regulation of cell-matrix adhesion Inferred from electronic annotation. Source: Compara positive regulation of fibroblast proliferation Inferred from electronic annotation. Source: Compara positive regulation of gene expression Inferred from direct assay Ref.7. Source: MGI regulation of erythrocyte differentiation Inferred from electronic annotation. Source: Compara response to virus Inferred from electronic annotation. Source: Compara type B pancreatic cell development Inferred from electronic annotation. Source: Compara
Cellular_component	cyclin-dependent protein kinase holoenzyme complex Inferred from electronic annotation. Source: Compara cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell ruffle Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from electronic annotation. Source: EC kinase activity Inferred from direct assay Ref.7. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 326	326	Cyclin-dependent kinase 6		PRO_0000085790
Regions
	Domain	13 – 300	288	Protein kinase
	Nucleotide binding	19 – 27	9	ATP By similarity
Sites
	Active site	145	1	Proton acceptor By similarity
	Binding site	43	1	ATP By similarity
Amino acid modifications
	Modified residue	13	1	Phosphotyrosine By similarity
	Modified residue	24	1	Phosphotyrosine By similarity
	Modified residue	43	1	N6-acetyllysine By similarity
	Modified residue	49	1	Phosphothreonine By similarity
	Modified residue	70	1	Phosphothreonine By similarity
	Modified residue	177	1	Phosphothreonine By similarity
	Modified residue	264	1	N6-acetyllysine By similarity
	Modified residue	325	1	Phosphothreonine By similarity
Natural variations
	Natural variant	321	1	S → A in strain: SPRET/Ei.
Experimental info
	Mutagenesis	31	1	R → C: Enhanced kinase activity. Over-production of thymocytes and hematopoietic stem cells and progenitor cells. Ref.7
	Mutagenesis	43	1	K → M: Loss of kinase activity. Pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Q64261 [UniParc]. Last modified April 30, 2003. Version 2. Checksum: 127B7ECFFC54C3AC	FASTA	326	37,028
	10 20 30 40 50 60 MEKDSLSRAD QQYECVAEIG EGAYGKVFKA RDLKNGGRFV ALKRVRVQTS EEGMPLSTIR 70 80 90 100 110 120 EVAVLRHLET FEHPNVVRLF DVCTVSRTDR ETKLTLVFEH VDQDLTTYLD KVPEPGVPTE 130 140 150 160 170 180 TIKDMMFQLL RGLDFLHSHR VVHRDLKPQN ILVTSSGQIK LADFGLARIY SFQMALTSVV 190 200 210 220 230 240 VTLWYRAPEV LLQSSYATPV DLWSVGCIFA EMFRRKPLFR GSSDVDQLGK ILDIIGLPGE 250 260 270 280 290 300 EDWPRDVALP RQAFHSKSAQ PIEKFVTDID ELGKDLLLKC LTFNPAKRIS AYGALNHPYF 310 320 QDLERYKDNL NSHLPSNQST SELNTA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human-mouse comparative mapping of the genomic region containing CDK6: localization of an evolutionary breakpoint." Thomas J.W., Lee-Lin S.Q., Green E.D. Mamm. Genome 10:764-767(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: BALB/c, C57BL/6J and SPRET/Ei. Tissue: Testis.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Cecum.
[3]	"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 149-183. Strain: CBA. Tissue: Bone marrow.
[4]	"Identification of new protein kinase genes, similar to kinases of the cdc2 family and expressed in murine hematopoietic stem cells." Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V. Dokl. Akad. Nauk SSSR 324:893-897(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 149-183. Strain: CBA. Tissue: Bone marrow.
[5]	"Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6." Malumbres M., Sotillo R., Santamaria D., Galan J., Cerezo A., Ortega S., Dubus P., Barbacid M. Cell 118:493-504(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[6]	"Changes in motility, gene expression and actin dynamics: Cdk6-induced cytoskeletal changes associated with differentiation in mouse astrocytes." Slomiany P., Baker T., Elliott E.R., Grossel M.J. J. Cell. Biochem. 99:635-646(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL DIFFERENTIATION.
[7]	"CDK6 kinase activity is required for thymocyte development." Hu M.G., Deshpande A., Schlichting N., Hinds E.A., Mao C., Dose M., Hu G.F., Van Etten R.A., Gounari F., Hinds P.W. Blood 117:6120-6131(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN THYMOCYTE DEVELOPMENT, DISRUPTION PHENOTYPE, MUTAGENESIS OF ARG-31 AND LYS-43.
[8]	"Cdk6-dependent regulation of G(1) length controls adult neurogenesis." Beukelaers P., Vandenbosch R., Caron N., Nguyen L., Belachew S., Moonen G., Kiyokawa H., Barbacid M., Santamaria D., Malgrange B. Stem Cells 29:713-724(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN NEURON PRODUCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF132483 mRNA. Translation: AAD43504.1. AF132482 mRNA. Translation: AAD43503.1. AK078973 mRNA. Translation: BAC37489.1. X65068 mRNA. Translation: CAA46201.1.
IPI	IPI00128463.
PIR	PN0483.
RefSeq	NP_034003.1. NM_009873.2.
UniGene	Mm.31672. Mm.389058. Mm.399714.
3D structure databases
ProteinModelPortal	Q64261.
SMR	Q64261. Positions 9-301.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-24175N.
IntAct	Q64261. 2 interactions.
PTM databases
PhosphoSite	Q64261.
Proteomic databases
PaxDb	Q64261.
PRIDE	Q64261.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000042410; ENSMUSP00000037925; ENSMUSG00000040274. ENSMUST00000165117; ENSMUSP00000126024; ENSMUSG00000040274.
GeneID	12571.
KEGG	mmu:12571.
Organism-specific databases
CTD	1021.
MGI	MGI:1277162. Cdk6.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101791.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	Q64261.
KO	K02091.
OMA	GNSDVDQ.
OrthoDB	EOG4BZN2X.
Gene expression databases
ArrayExpress	Q64261.
Bgee	Q64261.
CleanEx	MM_CDK6.
Genevestigator	Q64261.
GermOnline	ENSMUSG00000040274. 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
NextBio	281678.
SOURCE	Search...

Entry information

Entry name

CDK6_MOUSE

Accession

Primary (citable) accession number: Q64261
Secondary accession number(s): Q9R1D2, Q9R1D3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	April 30, 2003
Last modified:	May 1, 2013
This is version 116 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program