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Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase
Keller, Tracy L,Zocco, Davide,Sundrud, Mark S,Hendrick, Margaret,Edenius, Maja,Yum, Jinah,Kim, Yeon-Jin,Lee, Hak-Kyo,Cortese, Joseph F,Wirth, Dyann F,Dignam, John David,Rao, Anjana,Yeo, Chang-Yeol,Maz Nature Publishing Group, a division of Macmillan P 2012 Nature chemical biology Vol.8 No.3
Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T<SUB>H</SUB>17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.
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
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: