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

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 inhibi...

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Detalles Bibliográficos
Autores principales: Li, Zhaobo, Zhou, Lihong, Prodromou, Chrisostomos, Savic, Velibor, Pearl, Laurence H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489699/
https://www.ncbi.nlm.nih.gov/pubmed/28636940
http://dx.doi.org/10.1016/j.celrep.2017.05.078
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author Li, Zhaobo
Zhou, Lihong
Prodromou, Chrisostomos
Savic, Velibor
Pearl, Laurence H.
author_facet Li, Zhaobo
Zhou, Lihong
Prodromou, Chrisostomos
Savic, Velibor
Pearl, Laurence H.
author_sort Li, Zhaobo
collection PubMed
description 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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spelling pubmed-54896992017-07-12 HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients Li, Zhaobo Zhou, Lihong Prodromou, Chrisostomos Savic, Velibor Pearl, Laurence H. Cell Rep Article 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. Cell Press 2017-06-20 /pmc/articles/PMC5489699/ /pubmed/28636940 http://dx.doi.org/10.1016/j.celrep.2017.05.078 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Zhaobo
Zhou, Lihong
Prodromou, Chrisostomos
Savic, Velibor
Pearl, Laurence H.
HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title_full HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title_fullStr HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title_full_unstemmed HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title_short HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients
title_sort hectd3 mediates an hsp90-dependent degradation pathway for protein kinase clients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489699/
https://www.ncbi.nlm.nih.gov/pubmed/28636940
http://dx.doi.org/10.1016/j.celrep.2017.05.078
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