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    The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild-type function. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.


    Emilie Leroy, Alexandra Dusa, Didier Colau, Amir Motamedi, Xavier Cahu, Céline Mouton, Lily J Huang, Andrew K Shiau, Stefan N Constantinescu. Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix. The Biochemical journal. 2016 Jun 1;473(11):1579-91

    PMID: 27029346

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