ArticleThe Biochemical journal2010
A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F).
Article in The Biochemical journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 44 citations in OpenAlex.
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- Molecular landscape of theBiomedical reports · 2023Article
- The Contribution ofInternational journal of molecular sciences · 2022Review
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- Baricitinib: From Rheumatoid Arthritis to COVID-19.Journal of clinical pharmacology · 2021Review
- Identification of aHemaSphere · 2021Article
- Janus Kinases in Leukemia.Cancers · 2021Review
- Nanoparticles Targeting STATs in Cancer Therapy.Cells · 2019Review
- Review
- Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid-Transfer Proteins.Advances in experimental medicine and biology · 2019Review
- p.Y317H is a newHaematologica · 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
- Coexistence of gain-of-function JAK2 germ line mutations with JAK2V617F in polycythemia vera.Blood · 2016Article
- Crystal Structure of the FERM-SH2 Module of Human Jak2.PloS one · 2016Article
- JAK2 tyrosine kinase phosphorylates and is negatively regulated by centrosomal protein Ninein.Molecular and cellular biology · 2015Article
- JAK-cytokine receptor recognition, unboxed.Nature structural & molecular biology · 2014Article
- Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses.The Biochemical journal · 2014Article
- Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure.PLoS computational biology · 2013Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
JAK2 (Janus tyrosine kinase 2) is important for signalling through many cytokine receptors, and a gain-of-function JAK2 mutation in its pseudokinase domain, V617F, has been implicated in Philadelphia chromosome-negative myeloproliferative neoplasms. How this mutation hyperactivates JAK2 is poorly understood. In the present paper we report our findings that the V617F mutation has little effect on the Vmax of JAK2 kinase activity, but lowers the Km value for substrates. Therefore under physiological conditions where the concentration level of substrates is presumably below saturation, JAK2(V617F) exhibits hyperactivation compared with wild-type JAK2. This lower Km of JAK2(V617F) towards substrates requires the JAK2 FERM (4.1/ezrin/radixin/moesin) domain, as deletion of the FERM domain abolished this effect. We also show that, in contrast with its positive role in JAK2(V617F) hyperactivation, the FERM domain in wild-type JAK2 is inhibitory. Deletion or mutations of the FERM domain resulted in increased basal JAK2 kinase activity. The results of the present study provide the biochemical basis for how V617F hyperactivates JAK2, and identifies novel regulating roles of the JAK2 FERM domain to control kinase activity at different activation states.
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