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 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.
Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada.
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Izrailit
Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada.
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Jaiswal
Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada.
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Zheng
Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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Moran
Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada.|Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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Reedijk
D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D018797:Cell Cycle Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D012097:Repressor Proteins; C474831:TRIB3 protein, human; C506234:USP9X protein, human; D017346:Protein Serine-Threonine Kinases; D043222:Ubiquitin Thiolesterase