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Lookup NU author(s): Stephen Hallett, Dr Martyna PastokORCiD, Dr Anita Wittner, Professor Steve Wedge, Professor Martin NobleORCiD, Professor Jane Endicott
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Hallett ST, Pastok MW, Morgan RML, Wittner A, Blundell KLIM, Felletar I, Wedge SR, Prodromou C, Noble MEM, Pearl LH, Endicott JA
Publication type: Article
Publication status: Published
Journal: Cell Reports
Year: 2017
Volume: 21
Issue: 5
Pages: 1386-1398
Print publication date: 31/10/2017
Online publication date: 31/10/2017
Acceptance date: 11/10/2017
Date deposited: 28/11/2017
ISSN (print): 2211-1247
ISSN (electronic): 2211-1247
Publisher: Elsevier
URL: https://doi.org/10.1016/j.celrep.2017.10.042
DOI: 10.1016/j.celrep.2017.10.042
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