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Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling

Junnian Wei, Kevin K. Leung, Charles Truillet, Davide Ruggero, James A. Wells, Michael J. Evans
doi: https://doi.org/10.1101/382929
Junnian Wei
1Department of Radiology and Biomedical Imaging, University of California San Francisco 505 Parnassus Ave, San Francisco CA 94143
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Kevin K. Leung
2Department of Pharmaceutical Chemistry, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
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Charles Truillet
3Imagerie Moleculaire In Vivo, INSERM, CEA, Univ. Paris Sud, CNRS, Universite Paris Saclay, CEA-Service Hospitalier Frederic Joliot, Orsay France, 94100
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Davide Ruggero
4Department of Urology, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
5Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
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James A. Wells
2Department of Pharmaceutical Chemistry, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
5Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
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  • For correspondence: jim.wells@ucsf.edu michael.evans@ucsf.edu
Michael J. Evans
1Department of Radiology and Biomedical Imaging, University of California San Francisco 505 Parnassus Ave, San Francisco CA 94143
2Department of Pharmaceutical Chemistry, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
5Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 505 Parnassus Ave, San Francisco CA 94143
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  • For correspondence: jim.wells@ucsf.edu michael.evans@ucsf.edu
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Abstract

Loss of the TSC1/TSC2 complex leads to constitutively high mTORC1 signaling; however, pharmacological inhibition of mTORC1 in this setting produces a broad spectrum of clinical responses. We report herein several cell surface proteins upregulated by inactivation of TSC1 that present therapeutic alternatives or adjuvants to direct mTORC1 inhibition. A proteomics screen revealed that TSC1 loss most dramatically induced the expression of neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). The survival of TSC1 null human cancer cells was dependent on NEP expression, and TSC1 mutation sensitized cells to biochemical inhibition of APN. Remarkably, NEP and APN upregulation occurred via a TSC2- and mTORC1-independent mechanism; therefore, the antiproliferative effects of mTORC1 inhibition could be augmented by co-suppression of APN activity.

Statement of significance These data introduce a non-canonical biological role for TSC1 beyond regulating mTORC1 signaling, which also enabled several immediately translatable therapeutic strategies for clinically problematic cells with TSC1 mutations.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 01, 2018.
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Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling
Junnian Wei, Kevin K. Leung, Charles Truillet, Davide Ruggero, James A. Wells, Michael J. Evans
bioRxiv 382929; doi: https://doi.org/10.1101/382929
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Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling
Junnian Wei, Kevin K. Leung, Charles Truillet, Davide Ruggero, James A. Wells, Michael J. Evans
bioRxiv 382929; doi: https://doi.org/10.1101/382929

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