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Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System

Lookup NU author(s): Stephen Hallett, Dr Martyna PastokORCiD, Dr Anita Wittner, Professor Steve Wedge, Professor Martin NobleORCiD, Professor Jane Endicott

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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Funding

Funder referenceFunder name
095605/Z/11/Z
C2115/A21421Cancer Research UK CRUK (closed comp)
MR/N009738/1Medical Research Council (MRC)

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