ArticleThe Biochemical journal2016
Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.International journal of hematology · 2026Review
- ROR1 protein: a pseudokinase at the crossroads of cancer progression and therapy.Molecular biology reports · 2026Review
- JAK2 46/1 (GGCC) Haplotype in Oncogenesis, as Risk Stratifier, and Indicator for Drug Resistance in Myeloproliferative Neoplasms.International journal of molecular sciences · 2025Review
- Recent advances and future perspectives in small molecule JAK2 inhibitors.Future medicinal chemistry · 2025Review
- 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
- Structural basis of Janus kinase trans-activation.Cell reports · 2023Article
- Penttinen syndrome-associated PDGFRB Val665Ala variant causes aberrant constitutive STAT1 signalling.Journal of cellular and molecular medicine · 2022Article
- 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
- Review
- Molecular dissection of Janus kinases as drug targets for inflammatory diseases.Frontiers in immunology · 2022Review
- Review
- Article
- Article
- Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.Cancer cell · 2019Article
- Prospects for pharmacological targeting of pseudokinases.Nature reviews. Drug discovery · 2019Review
- Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations.The Journal of allergy and clinical immunology · 2019Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.