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Ras, PI3K and mTORC2 - three's a crowd?

Stephen F Smith1, Shannon E Collins1, Pascale G Charest2

  • 1Department of Molecular & Cellular Biology, Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, USA.

Journal of Cell Science
|October 9, 2020
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Summary
This summary is machine-generated.

Ras oncogene signaling is complex. This review explores how Ras and PI3K (phosphatidylinositol 3-kinases) differentially regulate mTORC2 (mechanistic target of rapamycin complex 2) in cancer and normal cells.

Keywords:
Mechanistic target of rapamycin complex 2Phosphatidylinositol 3-kinaseRas GTPase

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Area of Science:

  • Oncology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Ras oncogenes are difficult to target therapeutically.
  • Mechanistic target of rapamycin complex 2 (mTORC2) is an evolutionarily conserved Ras effector involved in cell processes and oncogenesis.
  • Regulation of mTORC2 activity is not well understood, but phosphatidylinositol (3,4,5)-trisphosphate, produced by phosphatidylinositol 3-kinases (PI3Ks), is a proposed regulator.

Purpose of the Study:

  • To review evidence on the links between Ras, PI3K, and mTORC2.
  • To clarify the unclear relationship between Ras, PI3K, and mTORC2 in physiology and cancer.
  • To propose a model for how Ras and PI3K differentially regulate mTORC2.

Main Methods:

  • Literature review of existing studies on Ras, PI3K, and mTORC2 signaling.
  • Analysis of data suggesting Ras and PI3K as direct regulators of mTORC2.
  • Synthesis of information to propose a regulatory model.

Main Results:

  • Ras and PI3K are identified as direct regulators of mTORC2.
  • Ras activates mTORC2 at the plasma membrane.
  • PI3K activates mTORC2 in intracellular compartments, suggesting distinct pools of mTORC2 regulation.

Conclusions:

  • Ras and PI3K differentially regulate distinct pools of mTORC2 based on location (plasma membrane vs. intracellular).
  • The stimulus, cell type, and distinct mTORC2 pools influence regulatory mechanisms.
  • Understanding these diverse regulatory mechanisms is crucial for targeting Ras signaling in cancer.