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Molecular determinants of Ras-mTORC2 signaling

Stephen F Smith1, A F M Tariqul Islam2, Shoxruxxon Alimukhamedov2

  • 1Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.

The Journal of Biological Chemistry
|May 30, 2024
PubMed

Insights

This study reveals key residues in RasC protein that control its specific activation of mTORC2, impacting cell movement and aggregation in Dictyostelium. Understanding these Ras-mTORC2 pathway regulators deepens knowledge of eukaryotic cell signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic Target of Rapamycin Complex 2 (mTORC2) is a direct effector of Ras proteins, but its precise regulation remains unclear.
  • In Dictyostelium, RasC selectively activates mTORC2, mediating crucial cellular processes like chemotaxis and aggregation.
  • Previous work suggested Ras protein's Switch I (SWI) domain interacts with mTORC2 components.

Purpose of the Study:

  • To investigate the roles of specific residues within RasC's SWI, allosteric, and hypervariable regions (HVR) in mTORC2 activation.
  • To elucidate the molecular determinants governing RasC's specific activation of the Ras-mTORC2 pathway.
  • To understand how RasC's membrane localization influences pathway activation.

Main Methods:

  • Site-directed mutagenesis of RasC protein to alter specific residues.
  • Analysis of RasC-mTORC2 pathway activation in Dictyostelium.
  • Assessment of RasC's interaction with upstream regulators (RasGEF) and downstream effectors (mTORC2).
  • Investigation of RasC's membrane localization and its impact on signaling.

Main Results:

  • RasC SWI residue A31 regulates activation by the Aimless RasGEF, impacting aggregation.
  • RasC SWI residue T36, along with E38 and allosteric domain residues, is crucial for mTORC2 activation.
  • Conserved basic residues and prenylation site in the HVR are essential for membrane localization and subsequent RasC-mTORC2 pathway activation.
  • RasC's cAMP-induced activation and subsequent mTORC2 activation are dependent on its proper membrane localization.

Conclusions:

  • Identified specific RasC residues critical for mTORC2 pathway specificity in Dictyostelium.
  • Elucidated the interplay between RasC's domains (SWI, allosteric, HVR) and membrane localization in pathway regulation.
  • Provided new insights into the regulation of Ras signaling pathways in eukaryotic cells.
Keywords:
DictyosteliumHVRRasCallosteric domainhypervariable regionmTORmechanistic Target of Rapamycin complex 2switch I

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