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MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation

Mohamad-Ali Fawal1, Marta Brandt1, Nabil Djouder1

  • 1Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.

Developmental Cell
|March 31, 2015
PubMed

Insights

Microspherule protein 1 (MCRS1) links amino acids to mTORC1 activation by regulating Rheb localization. MCRS1 suppression inactivates mTORC1, impacting cancer and diabetes signaling.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Ras homolog enriched in brain (Rheb) is crucial for mechanistic target of rapamycin complex 1 (mTORC1) activation by growth factors and amino acids (AAs).
  • Growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator.
  • The precise role of AAs in Rheb activation remained unclear.

Purpose of the Study:

  • To identify the molecular link between amino acid sensing and Rheb/mTORC1 pathway activation.
  • To elucidate the mechanism by which amino acids regulate Rheb and subsequent mTORC1 signaling.

Main Methods:

  • Utilized small interference RNA (siRNA) in human cancer cells.
  • Employed an inducible-Cre/Lox system in mouse embryonic fibroblasts (MEFs).
  • Investigated Rheb localization, TSC2 interaction, and mTORC1 activity.

Main Results:

  • Identified microspherule protein 1 (MCRS1) as a key mediator linking AAs to mTORC1.
  • Demonstrated that MCRS1, in an AA-dependent manner, anchors Rheb to lysosome surfaces, facilitating mTORC1 assembly.
  • Showed that MCRS1 suppression or depletion leads to Rheb delocalization from lysosomes, increased Rheb/TSC2 interaction, and mTORC1 inactivation.

Conclusions:

  • MCRS1 is essential for amino acid-mediated mTORC1 activation.
  • MCRS1 functions by maintaining Rheb at the lysosome, enabling mTORC1 signaling.
  • Dysregulation of MCRS1 impacts Rheb/mTORC1 signaling, with implications for diseases like cancer and diabetes mellitus.

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