PMID- 26588989
OWN - NLM
STAT- MEDLINE
DCOM- 20160301
LR  - 20211203
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 29
IP  - 22
DP  - 2015 Nov 15
TI  - NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition.
PG  - 2362-76
LID - 10.1101/gad.265116.115 [doi]
AB  - 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.
CI  - (c) 2015 Yuan et al.; Published by Cold Spring Harbor Laboratory Press.
FAU - Yuan, Hai-Xin
AU  - Yuan HX
AD  - Key Laboratory of Molecular Medicine of Ministry of Education, Institutes of 
      Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 20032, 
      China; Department of Pharmacology and Moores Cancer Center, University of 
      California at San Diego, La Jolla, California 92130, USA.
FAU - Wang, Zhen
AU  - Wang Z
AD  - Key Laboratory of Molecular Medicine of Ministry of Education, Institutes of 
      Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 20032, 
      China;
FAU - Yu, Fa-Xing
AU  - Yu FX
AD  - Children's Hospital, Institutes of Biomedical Sciences, Fudan University, 
      Shanghai 20032, China; Department of Pharmacology and Moores Cancer Center, 
      University of California at San Diego, La Jolla, California 92130, USA.
FAU - Li, Fulong
AU  - Li F
AD  - Key Laboratory of Molecular Medicine of Ministry of Education, Institutes of 
      Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 20032, 
      China;
FAU - Russell, Ryan C
AU  - Russell RC
AD  - Department of Pharmacology and Moores Cancer Center, University of California at 
      San Diego, La Jolla, California 92130, USA.
FAU - Jewell, Jenna L
AU  - Jewell JL
AD  - Department of Pharmacology and Moores Cancer Center, University of California at 
      San Diego, La Jolla, California 92130, USA.
FAU - Guan, Kun-Liang
AU  - Guan KL
AD  - Department of Pharmacology and Moores Cancer Center, University of California at 
      San Diego, La Jolla, California 92130, USA.
LA  - eng
GR  - T32 CA121938/CA/NCI NIH HHS/United States
GR  - R35 CA196878/CA/NCI NIH HHS/United States
GR  - R01 GM051586/GM/NIGMS NIH HHS/United States
GR  - R35CA196878/CA/NCI NIH HHS/United States
GR  - R01GM51586/GM/NIGMS NIH HHS/United States
GR  - T32CA121938/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Enzyme Activation
MH  - Gene Deletion
MH  - Gene Knock-In Techniques
MH  - HEK293 Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mitogen-Activated Protein Kinases/genetics/*metabolism
MH  - Multiprotein Complexes/*metabolism
MH  - Osmotic Pressure/*physiology
MH  - Phosphorylation
MH  - Regulatory-Associated Protein of mTOR
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4691891
OTO - NOTNLM
OT  - NLK
OT  - Raptor
OT  - cancer
OT  - mTOR
OT  - stress response
EDAT- 2015/11/22 06:00
MHDA- 2016/03/02 06:00
PMCR- 2016/05/15
CRDT- 2015/11/22 06:00
PHST- 2015/11/22 06:00 [entrez]
PHST- 2015/11/22 06:00 [pubmed]
PHST- 2016/03/02 06:00 [medline]
PHST- 2016/05/15 00:00 [pmc-release]
AID - 29/22/2362 [pii]
AID - 10.1101/gad.265116.115 [doi]
PST - ppublish
SO  - Genes Dev. 2015 Nov 15;29(22):2362-76. doi: 10.1101/gad.265116.115.