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

Wei, J.; Leung, K. K.; Truillet, C.; Ruggero, D.; Wells, J. A.; Evans, M. J.

doi:10.1101/382929

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bioRxiv · 10.1101/382929

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

Wei, J.·Leung, K. K.·Truillet, C.·Ruggero, D.·Wells, J. A.·Evans, M. J.

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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.\n\nStatement of significanceThese 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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Wei, J., Leung, K. K., Truillet, C., Ruggero, D., Wells, J. A., Evans, M. J.. 2018-08-01. Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling. https://doi.org/10.1101/382929

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