Related Experiment Video

Updated: Mar 29, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

909

NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

Hai-Xin Yuan1, Zhen Wang2, Fa-Xing Yu3

  • 1Key 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.

Genes & Development
|November 22, 2015
PubMed

Insights

Nemo-like kinase (NLK) regulates the mechanistic target of rapamycin complex 1 (mTORC1) during stress. NLK inhibits mTORC1 by preventing its lysosomal localization, impacting cell growth control.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth, forming mTORC1 and mTORC2 complexes.
  • While growth factor and nutrient signaling pathways activating mTORC1 are well-studied, stress-induced regulation remains less understood.

Purpose of the Study:

  • To identify novel regulators of mTORC1 in response to cellular stress.
  • To elucidate the mechanism by which Nemo-like kinase (NLK) modulates mTORC1 activity under stress conditions.

Main Methods:

  • Investigated the role of NLK in mediating osmotic and oxidative stress signals impacting mTORC1.
  • Utilized genetic manipulation (Nlk deletion and Raptor phosphorylation mutants) to assess mTORC1 localization and activation.
  • Examined the direct phosphorylation of Raptor by NLK and its effect on Rag GTPase interaction.

Main Results:

  • Identified NLK as a crucial mediator of stress-induced mTORC1 inhibition.
  • Demonstrated that NLK phosphorylates Raptor at S863, disrupting mTORC1's lysosomal localization via the Rag GTPase.
  • Observed impaired mTORC1 inhibition in cells lacking Nlk or expressing Raptor S863 phosphorylation mutants under osmotic stress.

Conclusions:

  • NLK plays a significant role in the cellular stress response by inhibiting mTORC1.
  • NLK's mechanism involves direct phosphorylation of Raptor, disrupting mTORC1 recruitment to lysosomes.
  • This study reveals a novel pathway for stress-induced mTORC1 modulation.
Keywords:
NLKRaptorcancermTORstress response

More Related Videos

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases06:56

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

Published on: September 6, 2024

874
Oligopeptide Competition Assay for Phosphorylation Site Determination09:16

Oligopeptide Competition Assay for Phosphorylation Site Determination

Published on: May 18, 2017

9.0K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.3K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.7K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
9.2K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
13.9K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
20.7K