Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix

Emilie Leroy, Alexandra Dusa, Didier Colau, Amir Motamedi, Xavier Cahu, Céline Mouton, Lily J. Huang, Andrew K. Shiau, Stefan N. Constantinescu

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1579-1591
Number of pages13
JournalBiochemical Journal
Issue number11
StatePublished - Jun 1 2016


  • Inhibitor
  • JAK-STAT signalling
  • JAK2 V617F
  • Kinase
  • Myeloproliferative neoplasm (MPN)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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