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Li et al Cell Reports 2017.pdf (2.94 MB)

HECTD3 mediates an HSP90-dependent degradation pathway for protein kinase clients

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posted on 2023-06-09, 06:51 authored by Zhaobo Li, Lihong Zhou, Chrisostomos ProdromouChrisostomos Prodromou, Velibor Savic, Laurence PearlLaurence Pearl
Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF. The first requires CUL5, Elongin B, and Elongin C, while the second requires the E3 ligase HECTD3, which is also involved in the degradation of MASTL and LKB1. HECTD3 associates with HSP90 and CRAF in cells via its N-terminal DOC domain, which is mutationally disrupted in tumor cells with activated MAP kinase signaling. Our data implicate HECTD3 as a tumor suppressor modulating the activity of this important oncogenic signaling pathway.

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Publication status

  • Published

File Version

  • Published version

Journal

Cell Reports

ISSN

2211-1247

Publisher

Elsevier

Issue

12

Volume

19

Page range

2515-2528

Department affiliated with

  • Clinical and Experimental Medicine Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-06-22

First Open Access (FOA) Date

2017-06-22

First Compliant Deposit (FCD) Date

2017-06-22

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