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SLAP controls mTORC2 integrity via UBE3C-mediated non-degradative mLST8 ubiquitination to suppress colorectal

Rudy Mevizou1,2, Dana Naim1,2,3, Florent Cauchois1,3

  • 1CRBM, Université de Montpellier, CNRS, Montpellier, France.

Cell Death and Differentiation
|December 15, 2025
PubMed

Insights

Src-Like Adaptor Protein (SLAP) suppresses colorectal cancer (CRC) by regulating mTORC2 integrity. SLAP targets mLST8 for ubiquitination, inhibiting cancer cell growth and invasion, offering new therapeutic strategies for CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The mechanistic target of rapamycin complex 2 (mTORC2) pathway is implicated in colorectal cancer (CRC) cell growth and migration.
  • Dysregulation of mTORC2 signaling contributes to oncogenesis in CRC, but the precise mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the role of Src-Like Adaptor Protein (SLAP) in regulating mTORC2 signaling and its impact on CRC.
  • To identify the molecular mechanisms by which SLAP exerts its tumor-suppressive functions in CRC.

Main Methods:

  • Investigated SLAP's interaction with mTORC2 components, specifically mLST8.
  • Utilized ubiquitination assays to examine SLAP-mediated modification of mLST8.
  • Identified the E3 ubiquitin ligase UBE3C as a key interactor in the SLAP-UBE3C-mLST8 complex.
  • Assessed the functional impact of SLAP on CRC cell proliferation, invasion, and xenograft tumor growth.
  • Evaluated the effect of SLAP depletion on CRC cell sensitivity to mTOR inhibitors.

Main Results:

  • SLAP interacts with mLST8, promoting its non-degradative ubiquitination at specific lysine residues (K86, K215).
  • This ubiquitination by SLAP, facilitated by UBE3C, reduces mTORC2 complex integrity and downstream mTORC2-AKT signaling.
  • SLAP's inhibition of CRC cell growth and invasion is dependent on its ability to suppress mTORC2 signaling.
  • SLAP depletion in CRC xenografts increased mTORC2 activity and enhanced sensitivity to mTOR catalytic inhibitors.

Conclusions:

  • A novel SLAP-UBE3C-mLST8 axis regulates mTORC2 integrity, playing a tumor-suppressive role in colorectal cancer.
  • SLAP's regulation of mTORC2 represents a potential therapeutic target for colorectal cancer treatment.

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