SLAP controls mTORC2 integrity via UBE3C-mediated mLST8 ubiquitination to mediate its tumour suppressive function in colorectal cancer

The mechanistic target of rapamycin complex 2 (mTORC2) signaling pathway, which regulates cell growth and migration, exhibits oncogenic function in colorectal cancer (CRC). mTORC2 signaling is primarily activated by a complex assembly of mTOR, RICTOR, SIN1, and mLST8, but how dysregulation of this mechanism contributes to its oncogenic function remains elusive. Here, we show that the Src-Like Adaptor Protein (SLAP), a negative regulator of tyrosine kinase signaling receptors, controls mTORC2 integrity to mediate its tumor-suppressive function in CRC. Mechanistically, SLAP interacts with mLST8 and promotes non-degradative ubiquitination, thereby reducing mTORC2 integrity and mTORC2-AKT signaling. The E3 ubiquitin ligase UBE3C was identified as a novel SLAP interactor involved in this ubiquitination process. Functionally, SLAP inhibition of CRC cell growth and invasion was dependent upon mTORC2 signaling inhibition. In immunodeficient mice CRC xenografts, SLAP depletion enhanced mTORC2 activity and sensitized CRC cells to mTOR catalytic inhibitors. Thus, our study uncovers a novel SLAP-mediated ubiquitination mechanism of mTORC2 dysregulation with potential therapeutic utility in CRC.