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mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation
He, Long,Gomes, Ana P.,Wang, Xin,Yoon, Sang Oh,Lee, Gina,Nagiec, Michal J.,Cho, Sungyun,Chavez, Andre,Islam, Tasnia,Yu, Yonghao,Asara, John M.,Kim, Bo Yeon,Blenis, John Elsevier 2018 Molecular cell Vol.70 No.5
<P><B>Summary</B></P> <P>The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression. Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits a 14-3-3 interaction, a reduction of DNA binding, and nuclear exclusion. Mechanistically, this occurs by mTORC1-dependent suppression of nuclear signaling by the Foxk1 kinase, Gsk3. This pathway then regulates the expression of multiple genes associated with glycolysis and downstream anabolic pathways directly modulated by Foxk1 and/or by Foxk1-regulated expression of Hif-1α. Thus, Foxk1 mediates mTORC1-driven metabolic rewiring, and it is likely to be critical for metabolic diseases where improper mTORC1 signaling plays an important role.</P> <P><B>Highlights</B></P> <P> <UL> <LI> mTORC1 suppresses GSK3-dependent Foxk1 phosphorylation </LI> <LI> Foxk1 phosphorylation promotes 14-3-3 binding and nuclear exclusion </LI> <LI> Foxk1 transcriptionally regulates Hif1α expression </LI> <LI> Foxk1 and Hif1α contribute to mTORC1-regulated metabolic reprogramming </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production
Hine, Christopher,Kim, Hyo-Jeong,Zhu, Yan,Harputlugil, Eylul,Longchamp, Alban,Matos, Marina Souza,Ramadoss, Preeti,Bauerle, Kevin,Brace, Lear,Asara, John M.,Ozaki, C. Keith,Cheng, Sheue-yann,Singha, S Cell Press 2017 Cell metabolism Vol.25 No.6
<▼1><P><B>Summary</B></P><P>Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H<SUB>2</SUB>S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H<SUB>2</SUB>S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H<SUB>2</SUB>S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H<SUB>2</SUB>S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H<SUB>2</SUB>S production by GH. Mice lacking CGL failed to downregulate systemic T<SUB>4</SUB> metabolism and circulating IGF-1, revealing an essential role for H<SUB>2</SUB>S in the regulation of key longevity-associated hormones.</P></▼1><▼2><P><B>Highlights</B></P><P>•<P>Hepatic H<SUB>2</SUB>S production capacity is elevated in long-lived hypopituitary mouse models</P>•<P>Growth hormone (GH) represses hepatic H<SUB>2</SUB>S production post-transcriptionally</P>•<P>Thyroid hormone (TH) acts via TRβ to repress cystathionine γ-lyase and H<SUB>2</SUB>S levels</P>•<P>H<SUB>2</SUB>S negatively regulates circulating TH and IGF-1 levels</P></P></▼2><▼3><P>Reduced thyroid hormone (TH) and growth hormone (GH) activity are hallmarks of genetic models of longevity in mice. Here, Hine et al. find that TH and GH negatively regulate hepatic production of the longevity-associated gas hydrogen sulfide, which feeds back to negatively regulate circulating TH and IGF-1 levels.</P></▼3>
A Secreted Tyrosine Kinase Acts in the Extracellular Environment
Bordoli, Mattia R.,Yum, J.,Breitkopf, Susanne B.,Thon, Jonathan N.,Italiano, Joseph E.,Xiao, J.,Worby, C.,Wong, S.K.,Lin, G.,Edenius, M.,Keller, Tracy L.,Asara, John M.,Dixon, Jack E.,Yeo, C.Y.,Whitma Cell Press ; MIT Press 2014 Cell Vol.158 No.5
Although tyrosine phosphorylation of extracellular proteins has been reported to occur extensively in vivo, no secreted protein tyrosine kinase has been identified. As a result, investigation of the potential role of extracellular tyrosine phosphorylation in physiological and pathological tissue regulation has not been possible. Here, we show that VLK, a putative protein kinase previously shown to be essential in embryonic development, is a secreted protein kinase, with preference for tyrosine, that phosphorylates a broad range of secreted and ER-resident substrate proteins. We find that VLK is rapidly and quantitatively secreted from platelets in response to stimuli and can tyrosine phosphorylate coreleased proteins utilizing endogenous as well as exogenous ATP sources. We propose that discovery of VLK activity provides an explanation for the extensive and conserved pattern of extracellular tyrosine phosphophorylation seen in vivo, and extends the importance of regulated tyrosine phosphorylation into the extracellular environment. PaperClip:
A Secreted Tyrosine Kinase Acts in the Extracellular Environment
Bordoli, Mattia R.,Yum, J.,Breitkopf, Susanne B.,Thon, Jonathan N.,Italiano, Joseph E.,Xiao, J.,Worby, C.,Wong, S.K.,Lin, G.,Edenius, M.,Keller, Tracy L.,Asara, John M.,Dixon, Jack E.,Yeo, C.Y.,Whitma Cell Press ; MIT Press 2014 Cell Vol.159 No.4