ArticleProceedings of the National Academy of Sciences of the United States of America2015
ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 107 citations in OpenAlex.
- Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.Nature communications · 2023Trial
- Review
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- NRIR promotes immune escape in hepatocellular cancer by regulating IFNγ-induced PD-L1 expression.Journal of advanced research · 2025Article
- Molecular Dynamics Simulation Analysis of JAK1 Initial Activation: Phosphorylation-Induced Conformational Dynamics and Domain Interactions.Life (Basel, Switzerland) · 2025Article
- Malignant JAK-signaling: at the interface of inflammation and malignant transformation.Leukemia · 2025Review
- Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling.Science advances · 2024Article
- Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies.International journal of molecular sciences · 2023Article
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling.International journal of molecular sciences · 2023Article
- The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms.Biomolecules · 2023Review
- Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Review
- Looking lively: emerging principles of pseudokinase signaling.Trends in biochemical sciences · 2022Review
- Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.Life science alliance · 2022Article
- Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands.Journal of medicinal chemistry · 2022Article
- Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies.ACS medicinal chemistry letters · 2022Article
- Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.Cell reports · 2022Article
- JAK2 in Myeloproliferative Neoplasms: Still a Protagonist.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Review
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Pseudokinases lack conserved motifs typically required for kinase activity. Nearly half of pseudokinases bind ATP, but only few retain phosphotransfer activity, leaving the functional role of nucleotide binding in most cases unknown. Janus kinases (JAKs) are nonreceptor tyrosine kinases with a tandem pseudokinase-kinase domain configuration, where the pseudokinase domain (JAK homology 2, JH2) has important regulatory functions and harbors mutations underlying hematological and immunological diseases. JH2 of JAK1, JAK2, and TYK2 all bind ATP, but the significance of this is unclear. We characterize the role of nucleotide binding in normal and pathogenic JAK signaling using comprehensive structure-based mutagenesis. Disruption of JH2 ATP binding in wild-type JAK2 has only minor effects, and in the presence of type I cytokine receptors, the mutations do not affect JAK2 activation. However, JH2 mutants devoid of ATP binding ameliorate the hyperactivation of JAK2 V617F. Disrupting ATP binding in JH2 also inhibits the hyperactivity of other pathogenic JAK2 mutants, as well as of JAK1 V658F, and prevents induction of erythrocytosis in a JAK2 V617F myeloproliferative neoplasm mouse model. Molecular dynamic simulations and thermal-shift analysis indicate that ATP binding stabilizes JH2, with a pronounced effect on the C helix region, which plays a critical role in pathogenic activation of JAK2. Taken together, our results suggest that ATP binding to JH2 serves a structural role in JAKs, which is required for aberrant activity of pathogenic JAK mutants. The inhibitory effect of abrogating JH2 ATP binding in pathogenic JAK mutants may warrant novel therapeutic approaches.
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