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A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1

Liron Bar-Peled1, Lynne Chantranupong, Andrew D Cherniack

  • 1Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02142, USA.

Science (New York, N.Y.)
|June 1, 2013
PubMed

Insights

Researchers discovered GATOR, a complex that negatively regulates the Rag GTPases, which are crucial for cell growth signaling. Mutations in GATOR1 are linked to cancer, making mTORC1 signaling hyperactive and cells sensitive to rapamycin.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mTOR complex 1 (mTORC1) pathway is vital for cell growth, responding to nutrients like amino acids.
  • Amino acids signal through Rag GTPases, facilitating mTORC1 activation at the lysosome.
  • The existence of negative regulators for Rag GTPases was previously unknown.

Purpose of the Study:

  • To identify negative regulators of the Rag GTPases.
  • To elucidate the function of the GATOR complex in mTORC1 signaling.
  • To investigate the role of GATOR components in human cancer.

Main Methods:

  • Protein complex isolation and characterization (GATOR1 and GATOR2).
  • Genetic manipulation to inhibit GATOR subunits and assess mTORC1 signaling.
  • GTPase-activating protein (GAP) assays for Rag GTPases.
  • Analysis of GATOR1 mutations in human cancer cell lines.

Main Results:

  • GATOR, comprising GATOR1 and GATOR2 subcomplexes, interacts with Rag GTPases.
  • GATOR1 acts as a GTPase-activating protein (GAP) for RagA and RagB.
  • Inhibition of GATOR1 confers resistance to amino acid deprivation, while GATOR2 inhibition suppresses mTORC1 signaling.
  • GATOR1 components are mutated in human cancer, leading to hyperactive mTORC1 signaling and rapamycin sensitivity.

Conclusions:

  • GATOR is identified as a key negative regulator of Rag GTPases.
  • Dysregulation of Rag GTPase function, via GATOR mutations, contributes to cancer.
  • This discovery provides new insights into mTORC1 pathway regulation and its role in oncogenesis.

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