Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer

Expression of the Notch ligand JAG1 and Notch pathway activation promote poor prognosis, basal-like breast cancer. We have recently shown that the pseudokinase Tribbles homolog 3 (TRB3) regulates JAG1 expression in this malignancy. TRB3 is a stress and metabolic sensor, and here we show that nutrien...

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Bibliographic Details
Published in:	Oncogene Vol. 36; no. 8; pp. 1048 - 1057
Main Authors:	Izrailit, J, Jaiswal, A, Zheng, W, Moran, M F, Reedijk, M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-02-2017 Nature Publishing Group
Subjects:	101/58 631/67/1347 631/80/86/2366 96 96/1 96/106 96/95 Analysis Apoptosis Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinoma, Basal Cell - genetics Carcinoma, Basal Cell - metabolism Carcinoma, Basal Cell - pathology Care and treatment Cell Biology Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell metabolism Cell Proliferation Cell survival Cellular stress response Development and progression Diagnosis Endocytosis Endoplasmic reticulum Endoplasmic Reticulum Stress Female Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Health aspects Human Genetics Humans Innovations Internal Medicine Malignancy Medical prognosis Medicine Medicine & Public Health Molecular targeted therapy Oncology original-article Protein Binding Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Risk factors Signal Transduction Stress response Therapeutic targets Tumor Cells, Cultured Tumors Ubiquitin Ubiquitin Thiolesterase - genetics Ubiquitin Thiolesterase - metabolism Ubiquitin-proteasome system Ubiquitin-protein ligase Ubiquitination Canada
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Summary:	Expression of the Notch ligand JAG1 and Notch pathway activation promote poor prognosis, basal-like breast cancer. We have recently shown that the pseudokinase Tribbles homolog 3 (TRB3) regulates JAG1 expression in this malignancy. TRB3 is a stress and metabolic sensor, and here we show that nutrient deprivation or endoplasmic reticulum stress markedly upregulate TRB3, which serves as a scaffold for the deubiquitinase USP9x. USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation. These USP9x activities are confined to the signal-sending cell of a cell pair undergoing Notch signaling. We demonstrate that USP9x is required for TRB3 upregulation and Notch activation in response to cellular stress in basal-like breast cancer cells. These data suggest that TRB3 functions as a sensor of tumor microenvironmental stress and together with USP9x induces the cell survival and tumor-promoting activities of Notch. These findings identify a novel mechanism by which cancer cells survive in their hostile environment and provide potential therapeutic targets in breast cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2016.276