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

The Ras/mitogen-activated protein kinase (MAPK) pathway regulates a variety of cellular processes by activating specific transcriptional and translational programs. Ras/MAPK signaling promotes mRNA translation and protein synthesis, but the exact molecular mechanisms underlying this regulation remain poorly understood. Increasing evidence suggests that the mammalian target of rapamycin (mTOR) plays an essential role in this process. Here, we show that Raptor, an essential scaffolding protein of the mTOR complex 1 (mTORC1), becomes phosphorylated on proline-directed sites following activation of the Ras/MAPK pathway. We found that ERK1 and ERK2 interact with Raptor in cells and mediate its phosphorylation in vivo and in vitro. Using mass spectrometry and phosphospecific antibodies, we found three proline-directed residues within Raptor, Ser(8), Ser(696), and Ser(863), which are directly phosphorylated by ERK1/2. Expression of phosphorylation-deficient alleles of Raptor revealed that phosphorylation of these sites by ERK1/2 normally promotes mTORC1 activity and signaling to downstream substrates, such as 4E-BP1. Our data provide a novel regulatory mechanism by which mitogenic and oncogenic activation of the Ras/MAPK pathway promotes mTOR signaling.

Pubmed ID: 21071439

Authors

  • Carriere A
  • Romeo Y
  • Acosta-Jaquez HA
  • Moreau J
  • Bonneil E
  • Thibault P
  • Fingar DC
  • Roux PP

Journal

The Journal of biological chemistry

Publication Data

January 7, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK-078135

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Binding Sites
  • Cell Line
  • Cell Proliferation
  • Humans
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Phosphorylation
  • Proline
  • Proteins
  • TOR Serine-Threonine Kinases
  • ras Proteins