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cyclin-dependent kinase-6 (CDK6, PLSTIRE)
Function:
- serine/threonine-protein kinase
- role in control of the cell cycle & differentiation
- promotes G1/S transition
- phosphorylates RB1 & NPM1
- interacts with D-type G1 cyclins during interphase at G1 to form an RB1 kinase & controls entrance into the cell cycle
- cyclin D1 binding promotes enzyme activation by phosphorylation at Thr-177
- role in initiation & maintenance of cell cycle exit during cell differentiation
- prevents cell proliferation & negatively regulates cell differentiation, but is required for proliferation of specific cell types (e.g. erythroid & hematopoietic cells)
- essential for cell proliferation within the dentate gyrus of the hippocampus & the subventricular zone of the lateral ventricles
- required during thymocyte development
- promotes the neurogenesis, probably by modulating length of G1 phase
- promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, & enhanced motility during cell differentiation
- prevents myeloid differentiation by interfering with RUNX1 & reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors
- delays cellular senescence
- promotes proliferation of beta-cells in pancreatic islets of Langerhans
- may play a role in centrosome organization during the cell cycle phases
- activated by Thr-177 phosphorylation & Tyr-24 dephosphorylation (putative)
- rapidly down-regulated prior to cell differentiation (e.g erythroid & osteoblast)
- Thr-177 phosphorylation & Tyr-24 dephosphorylation promotes kinase activity
- binds to RUNX1, CDKN2D, FBXO7 & CDKN2C/p18-INK4c
- forms a cytoplasmic complex with Hsp90/HSP90AB1 & CDC37
- FBXO7-binding promotes D-type cyclin binding
Inhibition:
- inhibited by INK4 proteins (CDKN2C/p18-INK4c), aminopurvalanol, PD0332991, 4-(pyrazol-4-yl)-pyrimidines & fisetin, a flavonol inhibitor
Structure:
- belongs to the protein kinase superfamily, CMGC Ser/Thr protein kinase family, CDC2/CDKX subfamily
- contains 1 protein kinase domain
Compartment:
- cytoplasm, nucleus, cell projection, ruffle
- localized to the ruffling edge of spreading fibroblasts
- kinase activity only in nucleus
- localized to cytosol of neurons & with staining around either side of the nucleus (putative)
- present in cytosol & in the nucleus in interphase cells & at the centrosome during mitosis from prophase to telophase
Expression:
- expressed ubiquitously
- accumulates in squamous cell carcinomas, proliferating hematopoietic progenitor cells, beta-cells of pancreatic islets of Langerhans, & neuroblastomas
- reduced levels in differentiating cells
- induced by NANOG during S-phase entry
Polymorphism:
- genetic variations in CDK6 may contribute to the stature quantitative trait locus 11 [4]
Pharmacology:
- enhances beta-cells engraftment in pancreatic islets of Langerhans of diabetic patients
Pathology:
- interacts with Kaposi's sarcoma herpesvirus (KSHV) V-cyclin & herpesvirus saimiri (V- cyclin/ECLF2)
- the CDK6/V-cyclin complex phosphorylates NPM1 & thus leads to viral reactivation by reducing viral LANA levels
- down-regulated in response to enterovirus 71 (EV71) infection
- over-expressed in some leukemias & malignancies (including sarcoma, glioma, breast tumors, lymphoma & melanoma) as a consequence of nearby translocations
- defects in CDK6 associated with microcephaly 12 [5]
Interactions
molecular events
General
cyclin-dependent kinase (CDK)
human longevity protein
Properties
SIZE: entity length = 326 aa
MW = 37 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: acetylation site
SITE: N-TERMINUS
EFFECTOR-BOUND: acetyl
kinase domain
SITE: 13-300
MOTIF: ATP-binding site
NAME: ATP-binding site
SITE: 19-27
Tyr phosphorylation site {Y13}
Tyr phosphorylation site {Y24}
ATP-binding site
NAME: ATP-binding site
SITE: 43-43
Thr phosphorylation site {T49}
Thr phosphorylation site {T70}
aspartate residue {D145}
Thr phosphorylation site {T177}
Thr phosphorylation site {T325}
STATE: active state
References
- Solomon MJ.
The function(s) of CAK, the p34cdc2-activating kinase.
Trends Biochem Sci. 1994 Nov;19(11):496-500.
PMID: 7855894
- UniProt :accession Q00534
- NIEHS-SNPs
http://egp.gs.washington.edu/data/cdk6/
- OMIM :accession 612223
- OMIM :accession 616080
- UniProt PubMed refs
- PMID: 14985467
- PMID: 985467
- PMID: 15809340
- PMID: 809340
- PMID: 17431401
- PMID: 431401
- PMID: 20668294
- PMID: 668294
- PMID: 8114739
- PMID: 12833137
- PMID: 11828325
- PMID: 828325
- PMID: 16096642
- PMID: 096642
- PMID: 21038853
- PMID: 038853
- PMID: 9482106
- PMID: 23918663
Component-of
molecular complex
Databases & Figures
OMIM correlations
UniProt Q00534
Pfam PF00069
Entrez Gene 1021
Kegg hsa:1021
ENZYME 2.7.11.22
RB/E2F1 interactions