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Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain

Jun Zhan1, Frank Harwood1, Sara Ten Have2

  • 1Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

International Journal of Molecular Sciences
|September 28, 2024
PubMed

Insights

A novel rapamycin-resistant mTORC3 complex, containing ETV7, drives cancer cell proliferation. Inhibiting mTORC3 assembly by targeting ETV7-mTOR interactions may offer new cancer therapies.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is critical for cell growth, regulating processes like translation and metabolism.
  • mTOR functions within two main complexes, mTORC1 and mTORC2, which are well-characterized.
  • Rapamycin is a drug that inhibits mTORC1, but resistance can develop in cancer cells.

Purpose of the Study:

  • To identify and characterize a novel rapamycin-resistant mTOR complex.
  • To investigate the role of the ETS transcription factor ETV7 in this new complex.
  • To explore the therapeutic potential of targeting this complex in cancer treatment.

Main Methods:

  • Identification of a new mTOR complex, termed mTORC3, lacking canonical mTORC1/2 components.
  • Analysis of the interaction between ETV7 and mTOR within mTORC3.
  • Experimental manipulation of mTOR domains in rapamycin-resistant cancer cells.

Main Results:

  • mTORC3 was identified as a rapamycin-resistant complex containing ETV7, which binds to mTOR.
  • mTORC3 phosphorylates targets of both mTORC1 and mTORC2, conferring a proliferative advantage.
  • The FRB and LBE domains of mTOR interact with the PNT and ETS domains of ETV7, respectively.
  • Forced expression of the mTOR FRB domain restored rapamycin sensitivity in resistant cells.

Conclusions:

  • mTORC3 represents a novel mTOR complex associated with rapamycin resistance and enhanced tumor cell proliferation.
  • The interaction between ETV7 and mTOR is essential for mTORC3 assembly and function.
  • Targeting the ETV7-mTOR interaction offers a potential therapeutic strategy for mTORC3-positive cancers.
Keywords:
ETV7mTOC3mTORrapamycin

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