Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System
| العنوان: | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
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| المؤلفون: | Hallett, Stephen T, Pastok, Martyna W, Morgan, R Marc L, Wittner, Anita, Blundell, Katie L I M, Felletar, Ildiko, Wedge, Stephen R, Prodromou, Chrisostomos, Noble, Martin E M, Pearl, Laurence H, Endicott, Jane A |
| المصدر: | Cell Reports, Vol 21, Iss 5, Pp 1386-1398 (2017) Cell Reports |
| بيانات النشر: | Elsevier, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | palbociclib, Chaperonins, kinase, Pyridines, CDK, CIP/KIP, Aminopyridines, Hsp90, Cell Cycle Proteins, Article, Piperazines, Inhibitory Concentration 50, Adenosine Triphosphate, Cyclin D, Fluorescence Resonance Energy Transfer, chaperone, Humans, HSP90 Heat-Shock Proteins, ribociclib, lcsh:QH301-705.5, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Surface Plasmon Resonance, Cdc37, Kinetics, lcsh:Biology (General), Purines, INK, Benzimidazoles, biological phenomena, cell phenomena, and immunity, Cyclin-Dependent Kinase Inhibitor p27, Protein Binding |
| الوصف: | Summary Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions. Graphical Abstract Highlights • CDK inhibitors and D-type cyclins competitively sequester CDK4/6 from Cdc37-Hsp90 • Binding of ATP-competitive inhibitors causes CDK4/6 to be displaced from Cdc37-Hsp90 • Cancer-associated p16INK4a mutants distinguish CDK4 and CDK6 • A model for the assembly factor activity of CIP/KIP CDK inhibitors is proposed Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2211-1247 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::18074ddd03d88b2bf4d1ce9e6611abc6Test http://www.sciencedirect.com/science/article/pii/S2211124717314894Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....18074ddd03d88b2bf4d1ce9e6611abc6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22111247 |
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