NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

Hai Xin Yuan, Zhen Wang, Fa Xing Yu, Fulong Li, Ryan C. Russell, Jenna L. Jewell, Kun Liang Guan

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2362-2376
Number of pages15
JournalGenes and Development
Volume29
Issue number22
DOIs
StatePublished - Nov 15 2015

Fingerprint

Raptors
Phosphotransferases
Osmotic Pressure
mechanistic target of rapamycin complex 1
GTP Phosphohydrolases
Sirolimus
Growth
Intercellular Signaling Peptides and Proteins
Oxidative Stress

Keywords

  • Cancer
  • MTOR
  • NLK
  • Raptor
  • Stress response

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Yuan, H. X., Wang, Z., Yu, F. X., Li, F., Russell, R. C., Jewell, J. L., & Guan, K. L. (2015). NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. Genes and Development, 29(22), 2362-2376. https://doi.org/10.1101/gad.265116.115

NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. / Yuan, Hai Xin; Wang, Zhen; Yu, Fa Xing; Li, Fulong; Russell, Ryan C.; Jewell, Jenna L.; Guan, Kun Liang.

In: Genes and Development, Vol. 29, No. 22, 15.11.2015, p. 2362-2376.

Research output: Contribution to journalArticle

Yuan, HX, Wang, Z, Yu, FX, Li, F, Russell, RC, Jewell, JL & Guan, KL 2015, 'NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition', Genes and Development, vol. 29, no. 22, pp. 2362-2376. https://doi.org/10.1101/gad.265116.115
Yuan, Hai Xin ; Wang, Zhen ; Yu, Fa Xing ; Li, Fulong ; Russell, Ryan C. ; Jewell, Jenna L. ; Guan, Kun Liang. / NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. In: Genes and Development. 2015 ; Vol. 29, No. 22. pp. 2362-2376.
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