2015
DOI: 10.1101/gad.265116.115
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NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

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 me… Show more

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Cited by 45 publications
(42 citation statements)
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“…4B). It has been reported that Ser 863, Ser 859 phosphorylation of Raptor by several kinases in response to different conditions, leading to a decrease of mTORC1 activity (Dunlop et al 2014; Stretton et al, 2015; Yuan et al 2015) because of reduced interaction between mTOR and Raptor (Stretton et al, 2015). However, structural analysis shows that Ser 859 of Raptor is located within the WD40 repeat domain and would have no direct contact with mTOR.…”
Section: Discussionmentioning
confidence: 99%
“…4B). It has been reported that Ser 863, Ser 859 phosphorylation of Raptor by several kinases in response to different conditions, leading to a decrease of mTORC1 activity (Dunlop et al 2014; Stretton et al, 2015; Yuan et al 2015) because of reduced interaction between mTOR and Raptor (Stretton et al, 2015). However, structural analysis shows that Ser 859 of Raptor is located within the WD40 repeat domain and would have no direct contact with mTOR.…”
Section: Discussionmentioning
confidence: 99%
“…Recently, we have discovered that nemo-like kinase (NLK), an atypical MAP kinase, can be activated by osmotic stress and plays a role in cellular response to osmotic stress [36]. In order to test the role of NLK, we used CRISPR/Cas9 system to knock out NLK by transfecting Cas9 and a guide RNA targeting NLK into HEK293A cells.…”
Section: Embo Reportsmentioning
confidence: 99%
“…Collectively, the above observations show that p38 and JNK are not required for YAP nuclear translocation in response to osmotic stress, indicating that other signaling molecules are involved in regulation of YAP upon osmotic stress. Recently, we have discovered that nemo-like kinase (NLK), an atypical MAP kinase, can be activated by osmotic stress and plays a role in cellular response to osmotic stress [36]. In order to test the role of NLK, we used CRISPR/Cas9 system to knock out NLK by transfecting Cas9 and a guide RNA targeting NLK into HEK293A cells.…”
Section: Embo Reportsmentioning
confidence: 99%
“…The mTORC1 kinase complex is a well-conserved regulator of growth pathway following the upstream signals of metabolic alterations, specifically sensing the nutrient administration [169]. Nevertheless, Raptor could solely decrease the liver steatosis in rodent models by interacting with PHLPP2 in an mTORC1-independent manner [170].…”
Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning
confidence: 99%
“…For example, GSK-3 could activate mTORC1 functionality via phosphorylating Raptor on Ser859 residue [171]; NLK, however, inhibits the mTORC1 activity by directly phosphorylating Raptor on the Ser863 residue under stressful conditions [169]. Besides, AMPK could largely depress the activity of mTORC1 by phosphorylation Raptor on Ser722 and Ser729, leading to cell cycle arrest and suppressed mitotic proliferation [172].…”
Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning
confidence: 99%