ArticleBiochemistry2010
The constitutive activation of Jak2-V617F is mediated by a π stacking mechanism involving phenylalanines 595 and 617.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Molecular Abnormalities and Associated Clinical Features in Polycythemia Vera.Medical sciences (Basel, Switzerland) · 2026Review
- Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank.Nature communications · 2024Article
- A novel germline hyperactivating JAK2 mutation L604F.Annals of hematology · 2023Article
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies.ACS medicinal chemistry letters · 2022Article
- Preclinical studies of Flonoltinib Maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2Blood cancer journal · 2022Article
- Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms.International journal of molecular sciences · 2022Review
- Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.Science (New York, N.Y.) · 2020Article
- Article
- Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations.The Journal of allergy and clinical immunology · 2019Article
- Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix.The Biochemical journal · 2016Article
- Review
- ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.Nature structural & molecular biology · 2014Article
- Molecular genetics of myelofibrosis and its associated disease phenotypes.Translational medicine @ UniSa · 2014Article
- Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases.Nature structural & molecular biology · 2013Article
- Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure.PLoS computational biology · 2013Article
- Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F.Nature structural & molecular biology · 2012Article
- A shift in the salt bridge interaction of residues D620 and E621 mediates the constitutive activation of Jak2-H538Q/K539L.Molecular and cellular biochemistry · 2012Article
- Janus kinase inhibitors: jackpot or potluck?Oncology reviews · 2012Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Somatic mutations in the Jak2 allele that lead to constitutive kinase activation of the protein have been identified in human disease conditions such as the myeloproliferative neoplasms (MPNs). The most common mutation in these patients is a V617F substitution mutation, which is believed to play a causative role in the MPN pathogenesis. As such, identifying the molecular basis for the constitutive activation of Jak2-V617F is important for understanding its clinical implications and potential treatment. Here, we hypothesized that conversion of residue 617 from Val to Phe resulted in the formation of novel π stacking interactions with neighboring Phe residues. To test this, we first examined the Jak2 structure via molecular modeling and identified a potential π stacking interaction between F594, F595, and F617. Disruption of this interaction through site-directed mutagenesis impaired Jak2 autophosphorylation, Jak2-dependent gene transcription, and in vitro kinase activity of the Jak2-V617F protein. Further, substitution of F594 and F595 with Trp did not affect Jak2 function significantly, but replacement with charged residues did, showing the importance of aromaticity and hydropathy index conservation at these positions. Using molecular dynamics (MD) simulations, we found that the π stacking interaction between residues 595 and 617 in the Jak2-V617F protein was of much greater energy and conformed to the properties of π stacking, relative to the Jak2-WT or Jak2-V617F/F594A/F595A. In summary, we have identified a π stacking interaction between F595 and F617 that is specific to and is critical for the constitutive activation of Jak2-V617F.
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