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Molecular & Cellular Proteomics

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Profiling the surfaceome identifies therapeutic targets for cells with hyperactive mTORC1 signaling

View ORCID ProfileJunnian Wei, Kevin Leung, Charles Truillet, Davide Ruggero, James Wells and View ORCID ProfileMichael J. Evans  Correspondence email
Molecular & Cellular Proteomics December 2, 2019, mcp.RA119.001785; https://doi.org/10.1074/mcp.RA119.001785
Junnian Wei
University of California, San Francisco, United States
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Kevin Leung
University of California, San Francisco, United States
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Charles Truillet
Imagerie Moleculaire In Vivo, INSERM, CEA, France
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Davide Ruggero
Medicine - Urology, University of California, San Francisco, United States
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James Wells
University of California, San Francisco, United States
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Michael J. Evans
Radiology, University of California, San Francisco, United States
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  • For correspondence: michael.evans@ucsf.edu
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Abstract

Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1-/- versus Tsc1+/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1-/- cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN.  In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.

  • Cancer Biology*
  • Cancer therapeutics
  • Cell biology*
  • Drug targets*
  • Membranes*
  • Mouse models
  • SILAC

Footnotes

  • Author contributions: J. Wei and M.J.E. designed research; J. Wei, K.L., and C.T. performed research; J. Wei, K.L., D.R., and M.J.E. analyzed data; J. Wei, K.L., and M.J.E. wrote the paper; D.R. and J. Wells contributed new reagents/analytic tools.

  • Received September 18, 2019.
  • Revision received November 4, 2019.
  • Accepted December 2, 2019.
  • Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
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Profiling the surfaceome identifies therapeutic targets for cells with hyperactive mTORC1 signaling
Junnian Wei, Kevin Leung, Charles Truillet, Davide Ruggero, James Wells, Michael J. Evans
Molecular & Cellular Proteomics December 2, 2019, mcp.RA119.001785; DOI: 10.1074/mcp.RA119.001785

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Profiling the surfaceome identifies therapeutic targets for cells with hyperactive mTORC1 signaling
Junnian Wei, Kevin Leung, Charles Truillet, Davide Ruggero, James Wells, Michael J. Evans
Molecular & Cellular Proteomics December 2, 2019, mcp.RA119.001785; DOI: 10.1074/mcp.RA119.001785
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