Mechanisms of constitutive activation of janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations

Tai Sung Lee*, Ma Wanlong, Xi Zhang, Francis Giles, Hagop Kantarjian, Maher Albitar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Background: The tyrosine kinase Janus kinase 2 (JAK2) is important in triggering nuclear translocation and regulation of target genes expression through signal transducer and activator of transcription pathways. The valine-to-phenylalanine mutation at amino acid 617 (V617F), which results in the deregulation of JAK2, has been implicated in the oncogenesis of chronic myeloproliferative disease. However, both the mechanism of JAK2 autoinhibition and the mechanism of V617F constitutive activation remain unclear. METHOD: In this work, the authors used molecular dynamics simulation techniques to establish plausible mechanisms of JAK2 autoinhibition and V617F constitutive activation at the atomic level. Results: In wild- type JAK2, the activation loop of JAK2-homology domain 1 (JH1) is pulled toward the JH1/JH2 interface through interactions with key residues of JH2, especially S591, F595, and V617, and stabilizes the inactivated form of JH1. In the case of V617F, through the aromatic ring-ring stacking interaction, F617 blocks the interaction of JH1 the activation loop, S591, and F595, thus causing the JH1 activation loop to move back to its activated form. Conclusions: The current results indicated that this simulation-derived mechanism of JAK2 autoregulation is consistent with current available experimental evidence and may lead to a deeper understanding of JAK2 and other kinase systems that are regulated by pseudokinases.

Original languageEnglish (US)
Pages (from-to)1692-1700
Number of pages9
Issue number8
StatePublished - Apr 15 2009


  • JAK2
  • Kinase
  • Molecular dynamics
  • Simulation
  • V617F

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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