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Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling
- Source :
- The Journal of allergy and clinical immunology, Vol. 144, no. 1, p. 224-235 (2019)
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Background Janus kinase (JAK) 2 plays pivotal roles in signaling by several cytokine receptors. The mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the mutant would be ideal for treating these pathologies by sparing essential JAK2 functions. Objective We characterize inhibitory strategies for JAK2 V617F and assess their effect on physiologic signaling by distinct cytokine receptors. Methods Through structure-guided mutagenesis, we assessed the role of key residues around F617 and used a combination of cellular and biochemical assays to measure the activity of JAKs in reconstituted cells. We also assessed the effect of several specific JAK2 V617F inhibitory mutations on receptor dimerization using the NanoBiT protein complementation approach. Results We identified a novel Janus kinase homology 2 (JH2) αC mutation, A598F, which is suggested to inhibit the aromatic stacking between F617 with F594 and F595. Like other JAK2 V617F inhibitory mutations, A598F decreased oncogenic activation and spared cytokine activation while preventing JAK2 V617F–promoted erythropoietin receptor dimerization. Surprisingly, A598F and other V617F-inhibiting mutations (F595A, E596R, and F537A) significantly impaired IFN-γ signaling. This was specific for IFN-γ because the inhibitory mutations preserved responses to ligands of a series of receptor complexes. Similarly, homologous mutations in JAK1 prevented signaling by IFN-γ. Conclusions The JH2 αC region, which is required for JAK2 V617F hyperactivation, is crucial for relaying cytokine-induced signaling of the IFN-γ receptor. We discuss how strategies aiming to inhibit JAK2 V617F could be used for identifying inhibitors of IFN-γ signaling.
- Subjects :
- IFNGR
0301 basic medicine
Immunology
Cell Line
Cytokine receptor signaling
JAK2 V617F
Mice
03 medical and health sciences
0302 clinical medicine
hemic and lymphatic diseases
Animals
Humans
Immunology and Allergy
IL-2 receptor
Receptors, Cytokine
Receptor
Janus Kinases
Janus kinase 1
Chemistry
Janus Kinase 2
Cell biology
Erythropoietin receptor
Myeloproliferative disorders
JAK1
kinases
030104 developmental biology
Tyrosine kinase 2
030220 oncology & carcinogenesis
Mutation
STAT protein
Cytokine receptor
Janus kinase
Signal Transduction
Subjects
Details
- ISSN :
- 00916749
- Volume :
- 144
- Database :
- OpenAIRE
- Journal :
- Journal of Allergy and Clinical Immunology
- Accession number :
- edsair.doi.dedup.....01fc5c065721b79e07d5b92854bec4b7