NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

Genes Dev. 2015 Nov 15;29(22):2362-76. doi: 10.1101/gad.265116.115.

Abstract

The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response.

Keywords: NLK; Raptor; cancer; mTOR; stress response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Enzyme Activation
  • Gene Deletion
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Multiprotein Complexes / metabolism*
  • Osmotic Pressure / physiology*
  • Phosphorylation
  • Regulatory-Associated Protein of mTOR
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases