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ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1)

Audrey Carriere1, Yves Romeo, Hugo A Acosta-Jaquez

  • 1Department of Pathology, Université de Montréal, Montréal, Québec H3C 3J7, Canada.

The Journal of Biological Chemistry
|November 13, 2010
PubMed

Insights

The Ras/MAPK pathway activates mTORC1 signaling by phosphorylating Raptor, a key protein. This phosphorylation promotes protein synthesis, linking Ras/MAPK pathway activation to mTOR signaling.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • The Ras/mitogen-activated protein kinase (MAPK) pathway is crucial for cellular processes, including mRNA translation and protein synthesis.
  • The precise molecular mechanisms by which Ras/MAPK signaling regulates translation are not fully understood.
  • Mammalian target of rapamycin (mTOR) is increasingly recognized for its role in this regulatory process.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking Ras/MAPK pathway activation to mTOR signaling.
  • To investigate the role of Raptor, a component of mTOR complex 1 (mTORC1), in this pathway.
  • To identify specific phosphorylation events on Raptor mediated by Ras/MAPK signaling.

Main Methods:

  • Investigated the interaction between ERK1/2 (kinases in the MAPK pathway) and Raptor.
  • Utilized mass spectrometry and phosphospecific antibodies to identify phosphorylated sites on Raptor.
  • Employed phosphorylation-deficient Raptor alleles to assess the functional impact of identified phosphorylation sites.

Main Results:

  • Raptor is phosphorylated on proline-directed sites (Ser8, Ser696, Ser863) by ERK1/2 following Ras/MAPK pathway activation.
  • ERK1 and ERK2 directly interact with and phosphorylate Raptor both in vitro and in vivo.
  • Phosphorylation of these specific sites on Raptor by ERK1/2 enhances mTORC1 activity and downstream signaling to substrates like 4E-BP1.

Conclusions:

  • Ras/MAPK pathway activation promotes mTORC1 signaling through direct phosphorylation of Raptor by ERK1/2.
  • This provides a novel regulatory mechanism connecting mitogenic and oncogenic Ras/MAPK signaling to mTOR-mediated protein synthesis.
  • Understanding this crosstalk is vital for comprehending cellular growth and disease states driven by these pathways.

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