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

Area of Science:

• Cellular Biology
• Molecular Oncology
• Signal Transduction

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and is often dysregulated in cancer.
• Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1) inhibits mTORC1, and its expression can override arginine-mediated activation.
• Cancer cells frequently face nutrient-deprived conditions, suggesting alternative regulatory mechanisms for CASTOR1.

Purpose of the Study:

• To investigate the regulation of CASTOR1 expression and its impact on mTORC1 signaling in cancer.
• To identify novel mechanisms controlling mTORC1 activation beyond nutrient availability.
• To explore the role of CASTOR1 regulation in breast cancer progression.

Main Methods:

• Investigated K29-linked polyubiquitination and degradation of CASTOR1 using the E3 ubiquitin ligase RNF167.
• Analyzed the effect of AKT phosphorylation at S14 on CASTOR1 binding to RNF167 and MIOS.
• Assessed mTORC1 activation, CASTOR1 degradation, and breast cancer progression in relevant cell models.

Main Results:

• RNF167 mediates K29-linked polyubiquitination and subsequent degradation of CASTOR1.
• AKT phosphorylates CASTOR1 at S14, enhancing its interaction with RNF167, promoting degradation, and reducing MIOS binding.
• Degradation of CASTOR1 by AKT and RNF167 activates mTORC1 independently of arginine, contributing to breast cancer progression.
• Identified a novel AKT- and RNF167-dependent pathway for mTORC1 activation.

Conclusions:

• AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways.
• RNF167-mediated CASTOR1 degradation is a key mechanism for mTORC1 activation in cancer, independent of arginine.
• Targeting RNF167 represents a potential therapeutic strategy for mTORC1-driven cancers, including breast cancer.