HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients.

Abstract:

: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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Li Z,Zhou L,Prodromou C,Savic V,Pearl LH

doi

10.1016/j.celrep.2017.05.078

subject

Has Abstract

pub_date

2017-06-20 00:00:00

pages

2515-2528

issue

12

issn

2211-1247

pii

S2211-1247(17)30752-0

journal_volume

19

pub_type

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