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 Repjournal_title
Cell reportsauthors
Li Z,Zhou L,Prodromou C,Savic V,Pearl LHdoi
10.1016/j.celrep.2017.05.078subject
Has Abstractpub_date
2017-06-20 00:00:00pages
2515-2528issue
12issn
2211-1247pii
S2211-1247(17)30752-0journal_volume
19pub_type
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