ArticleThe Journal of biological chemistry2009
A JAK2 interdomain linker relays Epo receptor engagement signals to kinase activation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 42 citations in OpenAlex.
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Clinical features and prognosis of pediatric acute lymphocytic leukemia with JAK-STAT pathway genetic abnormalities: a case series.Annals of hematology · 2023Article
- Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.Nature communications · 2023Article
- 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
- Growth Hormone Receptor Regulation in Cancer and Chronic Diseases.Frontiers in endocrinology · 2020Review
- Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm.Leukemia · 2017Article
- Integration of ruxolitinib into dose-intensified therapy targeted against a novel JAK2 F694L mutation in B-precursor acute lymphoblastic leukemia.Pediatric blood & cancer · 2017Article
- Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition.Leukemia · 2017Review
- Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase.Frontiers in endocrinology · 2017Review
- Article
- Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix.The Biochemical journal · 2016Article
- Mpl traffics to the cell surface through conventional and unconventional routes.Traffic (Copenhagen, Denmark) · 2014Article
- The molecular regulation of Janus kinase (JAK) activation.The Biochemical journal · 2014Review
- Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.Nature structural & molecular biology · 2014Article
- Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
- Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases.Nature structural & molecular biology · 2013Article
- The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection.Kidney international · 2013Article
- Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure.PLoS computational biology · 2013Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
JAK2 (Janus kinase 2) is essential for cytokine receptor signaling, and several lines of evidence support a causal role of an activating JAK2 mutation in myeloproliferative disorders. JAK2 activity is autoinhibited by its pseudokinase domain in the basal state, and the inhibition is released by cytokine stimulation; how engagement of the cognate receptor triggers this release is unknown. From a functional screen for gain-of-function JAK2 mutations, we discovered 13 missense mutations, nine in the pseudokinase domain and four in the Src homology 2 (SH2)-pseudokinase domain linker. These mutations identified determinants for autoinhibition and inducible activation in JAK2. Two of the mutants, K539I and N622I, resulted in erythrocytosis in mice. Scanning mutagenesis of the SH2-pseudokinase domain linker indicated that its N-terminal part was essential for interaction of JAK2 with the Epo receptor, whereas certain mutations in the C-terminal region conferred constitutive activation. We further showed that substitutions for Glu(543)-Asp(544) in this linker or Leu(611), Arg(683), or Phe(694) in the hinge proximal region of the pseudokinase domain resulted in activated JAK2 mutants that could not be further stimulated by Epo. These results suggest that the SH2-pseudokinase domain linker acts as a switch that relays cytokine engagement to JAK2 activation by flexing the pseudokinase domain hinge.
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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.