The FBXW7-SHOC2-Raptor axis controls the cross-talks between RAS/ERK and mTORC1 signaling pathways

FBXW7 is a tumor suppressive E3 ubiquitin ligase, whereas the RAS/ERK and mTORC1 are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. While SHOC2 is a scaffold protein that activates RAS/ERK signal, whether and how SHOC2 regulates mTORC1 is unknown. Here we showed that SHOC2 is a novel substrate of FBXW7. Upon phosphorylation on Thr507 by ATR, SHOC2 is recognized by FBXW7 for targeted ubiquitylation and degradation. Consistently, SHOC2-induced RAS/ERK activation and cell growth are inhibited by FBXW7. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 and induce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in human pancreatic cancer, which correlated with poor patient survival, and multiple SHOC2 mutations were found in human lung cancer tissues with the gain-of-function activity. Collectively, our study established that SHOC2-Raptor interaction triggers negative cross-talk between the RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways via targeting SHOC2 for ubiquitylation and degradation.