The V617F mutation in JAK2 renders myeloid cells more sensitive to IL-6-mediated gp130 signaling
Schurse, H.; Szymanski de Toledo, M.; Kuster, A.; Koschmieder, S.; Caduc, M. J.; Dusterhoft, S.; Muller-Newen, G.
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The somatic V617F mutation in the pseudokinase domain of JAK2 (JAK2VF) causes various phenotypes of myeloproliferative neoplasms (MPN). By interacting with cytokine receptors such as those for erythropoietin (EPO) or thrombopoietin (TPO), JAK2VF induces ligand-independent dimerization and activation, leading to deregulated blood cell production, cytokine hypersensitivity, and inflammatory cytokine release. Interleukin-6 (IL-6), a key mediator of inflammatory symptoms in MPN, signals via homodimers of the gp130 receptor. We investigated whether JAK2VF alters gp130 dimerization and IL-6 sensitivity. Molecular dynamics simulations demonstrated that the JAK2VF pseudokinase domain forms more stable dimers than wild-type (WT) JAK2, potentially supporting gp130 tetramerization. In cell-based assays, IL-6 stimulation of JAK2VF+ cells induced stronger STAT3 activation than in JAK2-WT cells, reflecting enhanced IL-6 sensitivity. Moreover, JAK2VF expression elevated gp130 surface levels, dependent on the JAK2-binding motif in gp130. These findings indicate that JAK2VF promotes gp130 expression and dimerization, sensitizing mutant cells to IL-6. Thus, JAK2VF-driven amplification of IL-6/gp130 signaling may foster chronic inflammation and disease progression in MPN, representing a potential therapeutic target.
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