RT Journal Article
SR Electronic
T1 Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 382929
DO 10.1101/382929
A1 Junnian Wei
A1 Kevin K. Leung
A1 Charles Truillet
A1 Davide Ruggero
A1 James A. Wells
A1 Michael J. Evans
YR 2018
UL http://biorxiv.org/content/early/2018/08/01/382929.abstract
AB 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.