Phosphatase PTPN22 functions as an adaptor in the mTORC2 complex

Area of Science:

• Cellular Biology
• Molecular Signaling
• Biochemistry

Background:

• The mechanistic target of rapamycin (mTOR) kinase regulates cellular growth and metabolism.
• mTOR functions via two complexes: mTORC1 and mTORC2, with mTORC2 regulation being less understood.
• Identifying novel regulators of mTORC2 is critical for understanding cellular signaling.

Purpose of the Study:

• To identify novel proteins associated with mTORC2.
• To elucidate the role of PTPN22 in mTORC2 signaling and function.
• To investigate the mechanism by which PTPN22 influences mTORC2 activity.

Main Methods:

• Co-immunoprecipitation to identify mTORC2-associated proteins.
• Western blotting to assess AKT phosphorylation.
• Cellular assays and nude mouse xenografts to evaluate cell growth and survival.

Main Results:

• PTPN22 was identified as an mTORC2-associated protein.
• PTPN22 is essential for mTORC2/AKT axis activation, independent of cell lineage.
• PTPN22 acts as a scaffold protein promoting mSIN-RICTOR interaction, crucial for mTORC2 integrity, independent of its phosphatase activity.
• Loss of PTPN22 impairs AKT phosphorylation and cell growth/survival.

Conclusions:

• PTPN22 plays a critical, non-catalytic role in mTORC2 complex assembly and function.
• PTPN22 is essential for regulating the mTORC2/AKT pathway, impacting cell growth and survival.
• These findings reveal a novel function for PTPN22 in cellular homeostasis.