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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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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. |
format | Online Article Text |
id | pubmed-5489699 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
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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