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

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

Polymorphism

• genetic variations in CDK6 may contribute to the stature quantitative trait locus 11

Pharmacology

• enhances beta-cells engraftment in pancreatic islets of Langerhans of diabetic patients

More general terms

• cyclin-dependent kinase (CDK)
• human longevity protein

Component of

• CDK6/cyclin D complex

Database

• UniProt: http://www.uniprot.org/uniprot/Q00534.html
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1021
• OMIM: https://mirror.omim.org/entry/603368
• OMIM: https://mirror.omim.org/entry/612223
• OMIM: https://mirror.omim.org/entry/616080
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1021