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

MTORC1 is a well-known key regulator of macroautophagy/autophagy. However, the underlying regulatory mechanisms of MTORC1 activity remains elusive. We showed recently that SHOC2, a RAS activator, competes with MTOR for RPTOR (but not RICTOR) binding, leading to MTORC1 inactivation, autophagy induction and cell survival, whereas RPTOR competes with RAS for SHOC2 binding to inactivate RAS-MAPK and suppresses growth. Interestingly, SHOC2 is subjected to FBXW7 regulation. Upon growth stimulation, MAP2K1 phosphorylates SHOC2 on T507 to facilitate its binding with FBXW7B/FBXW7β for ubiquitination and degradation to terminate growth signaling, thus establishing a negative feedback loop. Human cancers with FBXW7 inactivation and SHOC2 overexpression would squeeze RPTOR from MTORC1, leading to MTORC1 inactivation and autophagy induction. Collectively, we propose a new mode of the FBXW7-SHOC2-RPTOR axis in control of MTORC1 activity that affects autophagy and cancer cell survival.