ArticleNature structural & molecular biology2011
The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling.
Article in Nature structural & molecular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers.
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Who cites it
126 citing papers in PubMed, 287 citations in OpenAlex.
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Allosteric inhibition of JAK2 with lysine-reactive compounds that bind the pseudokinase domain.European journal of medicinal chemistry · 2026Article
- Cytokine Landscapes, Immune Dysregulation, and Treatment Perspectives in Philadelphia-Negative Myeloproliferative Neoplasms: A Narrative Review.Journal of clinical medicine · 2025Review
- The transcription factor STAT3 and aging: an intermediate medium.Biogerontology · 2025Review
- Deep learning-guided discovery of selective JAK2-JH2 allosteric inhibitors: integration of MLP predictive modeling, BREED-based library design, and computational validation.Frontiers in chemistry · 2025Article
- Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors.Endocrine reviews · 2024Review
- Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance.Cancers · 2024Review
- Targeting the JAK2/STAT3 signaling pathway for chronic pain.Aging and disease · 2024Review
- A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance.Molecular oncology · 2024Article
- JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target.Frontiers in pharmacology · 2024Review
- Interplay between epigenetic and genetic alterations in inborn errors of immunity.Trends in immunology · 2023Review
- Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy.Cell communication and signaling : CCS · 2023Review
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation.International journal of molecular sciences · 2023Article
- Article
- The role of IL-6/JAK/STAT signal in female infertility caused by hydrosalpinx.Immunity, inflammation and disease · 2023Article
- Emerging functions of pseudoenzymes.The Biochemical journal · 2023Review
- Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer.Signal transduction and targeted therapy · 2023Review
- JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling.International journal of molecular sciences · 2023Article
66 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on byJH2 is active!2011
Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling. Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized mechanism to control basal activity and signaling of JAK2.
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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.