RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation

mTORC1, a central controller of cell proliferation in response to growth factors and nutrients, is dysregulated in cancer. Whereas arginine activates mTORC1, it is overridden by high expression of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Because cancer cells often encounter low levels of nutrients, an alternative mechanism might exist to regulate CASTOR1 expression. Here we show K29-linked polyubiquitination and degradation of CASTOR1 by E3 ubiquitin ligase RNF167. Furthermore, AKT phosphorylates CASTOR1 at S14, significantly increasing its binding to RNF167, and hence its ubiquitination and degradation, while simultaneously decreasing its affinity to MIOS, leading to mTORC1 activation. Therefore, AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways. Several cell types with high CASTOR1 expression are insensitive to arginine regulation. Significantly, AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 independent of arginine and promotes breast cancer progression. These results illustrate a mTORC1 regulating mechanism and identify RNF167 as a therapeutic target for mTORC1-dysregulated diseases. CASTOR1 is an arginine sensor that inhibits mTORC1 activation, for which this pathway is frequently dysregulated in cancers. Here the authors show that AKT and E3 ubiquitin ligase RNF167 mediate CASTOR1 phosphorylation and degradation to activate mTORC1 and promote tumorigenesis.

Automated summary

mTORC1, a central regulator of cell proliferation, is dysregulated in cancer due to the inhibition by CASTOR1, an arginine sensor. The phosphorylation and degradation of CASTOR1 by AKT and E3 ubiquitin ligase RNF167 activate mTORC1 independent of arginine, promoting tumorigenesis. This pathway provides a potential therapeutic target for mTORC1-dysregulated diseases.