The MTORC1-mediated autophagy is regulated by the FBXW7-SHOC2-RPTOR axis

Area of Science:

• Cellular Biology
• Molecular Oncology
• Signal Transduction

Background:

• MTORC1 (mechanistic target of rapamycin complex 1) is a critical regulator of autophagy.
• The precise mechanisms controlling MTORC1 activity are not fully understood.
• SHOC2, a RAS activator, and RPTOR, a component of MTORC1, interact with MTORC1 and RAS-MAPK pathways.

Purpose of the Study:

• To elucidate the regulatory mechanisms of MTORC1 activity.
• To investigate the role of the FBXW7-SHOC2-RPTOR axis in controlling MTORC1 signaling.
• To understand the implications for cancer cell survival and autophagy.

Main Methods:

• Investigated protein-protein interactions between SHOC2, MTOR, RPTOR, RICTOR, and RAS.
• Utilized FBXW7 and SHOC2 regulation studies, including phosphorylation and ubiquitination.
• Analyzed the effects of FBXW7 inactivation and SHOC2 overexpression in human cancers.

Main Results:

• SHOC2 competes with MTOR for RPTOR binding, inactivating MTORC1 and inducing autophagy.
• RPTOR competes with RAS for SHOC2 binding, inhibiting RAS-MAPK signaling.
• FBXW7 targets phosphorylated SHOC2 for degradation, creating a negative feedback loop for growth signaling.
• In cancers with FBXW7 inactivation and SHOC2 overexpression, RPTOR is displaced from MTORC1, leading to MTORC1 inactivation and autophagy.

Conclusions:

• A novel FBXW7-SHOC2-RPTOR axis controls MTORC1 activity.
• This axis modulates autophagy and influences cancer cell survival.
• Dysregulation of this axis in cancer contributes to MTORC1 inactivation and increased autophagy.