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Phosphatase PTPN22 functions as an adaptor in the mTORC2 complex

Keshav Gupta1,2, Nagalakshmi Kommineni1, Tanuja Bogadi1

  • 1Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Uppal, Hyderabad, Telangana, 500039, India.

EMBO Reports
|September 16, 2025
PubMed

Insights

Tyrosine phosphatase PTPN22 acts as a scaffold protein, essential for mTORC2 complex assembly and AKT pathway activation. This non-catalytic role of PTPN22 is crucial for cell growth and survival.

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.
Keywords:
AKTPTPN22RictormSINmTOR

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