ArticlePloS one2010
JAK2 V617F constitutive activation requires JH2 residue F595: a pseudokinase domain target for specific inhibitors.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 84 citations in OpenAlex.
- JAK2 46/1 (GGCC) Haplotype in Oncogenesis, as Risk Stratifier, and Indicator for Drug Resistance in Myeloproliferative Neoplasms.International journal of molecular sciences · 2025Review
- Review
- Structural basis of MPL activation by thrombopoietin.Blood vessels, thrombosis & hemostasis · 2024Article
- Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling.Science advances · 2024Article
- 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
- Molecular Pathogenesis of Myeloproliferative Neoplasms: From Molecular Landscape to Therapeutic Implications.International journal of molecular sciences · 2022Review
- Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation.Science (New York, N.Y.) · 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
- Review
- A typical acute lymphoblastic leukemia JAK2 variant, R683G, causes an aggressive form of familial thrombocytosis when germline.Leukemia · 2021Article
- Review
- Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core.Journal of medicinal chemistry · 2020Article
- Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.Science (New York, N.Y.) · 2020Article
- Recent insights regarding the molecular basis of myeloproliferative neoplasms.The Korean journal of internal medicine · 2020Review
- Article
- Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations.The Journal of allergy and clinical immunology · 2019Article
- Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.ACS medicinal chemistry letters · 2017Article
- Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition.Leukemia · 2017Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 alphaC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the alphaC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type.
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