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Regulation of mTORC1 complex assembly and signaling by GRp58/ERp57

Iliana Ramírez-Rangel1, Ismael Bracho-Valdés, Aleida Vázquez-Macías

  • 1Departamento de Farmacología CINVESTAV-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, 07000 Mexico D.F., Mexico.

Molecular and Cellular Biology
|February 16, 2011
PubMed

Insights

GRp58/ERp57 protein regulates the mammalian target of rapamycin complex 1 (mTORC1) assembly and activity. This protein

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) controls cell growth and survival through mTORC1 and mTORC2 complexes.
  • The molecular mechanisms governing mTORC1 and mTORC2 assembly are not fully understood.

Purpose of the Study:

  • To investigate the role of GRp58/ERp57 in the assembly and regulation of mTORC1.
  • To elucidate the molecular mechanisms underlying mTORC1 activation.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to assess protein levels and phosphorylation.
  • Knockdown and overexpression studies of GRp58/ERp57.
  • Cellular localization studies using immunofluorescence.

Main Results:

  • GRp58/ERp57 directly interacts with mTOR and preferentially with mTORC1.
  • GRp58/ERp57 knockdown reduces mTORC1 levels and activity, while overexpression enhances them.
  • GRp58/ERp57 influences mTORC1 activity through a redox-sensitive mechanism.
  • GRp58/ERp57 is found in the cytosol and associated with the endoplasmic reticulum (ER) alongside mTORC1 components.
  • Insulin and leucine stimulation decrease GRp58/ERp57's ER association and activate mTORC1.

Conclusions:

  • GRp58/ERp57 is crucial for mTORC1 assembly and positively regulates mTORC1 signaling.
  • GRp58/ERp57 functions in both the cytosol and at the cytosolic side of the ER to control mTORC1.
  • A redox-sensitive mechanism involving GRp58/ERp57 mediates mTORC1 activation.

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