{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T19:04:27Z","timestamp":1774983867337,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2009,2,4]],"date-time":"2009-02-04T00:00:00Z","timestamp":1233705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2009,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>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\u2010to\u2010phenylalanine 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHOD:<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>In wild\u2010type JAK2, the activation loop of JAK2\u2010homology 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\u2010ring 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>The current results indicated that this simulation\u2010derived 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. Cancer 2009. \u00a9 2009 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.24183","type":"journal-article","created":{"date-parts":[[2009,2,4]],"date-time":"2009-02-04T21:49:55Z","timestamp":1233784195000},"page":"1692-1700","source":"Crossref","is-referenced-by-count":24,"title":["Mechanisms of constitutive activation of Janus kinase 2\u2010V617F revealed at the atomic level through molecular dynamics 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