Janus kinase (JAK) 2 regulation and the novel activating mutation, JAK2R546Q
Corbo, Lana Marie
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Janus kinase (JAK) 2 is a critical secondary signaling protein and is ubiquitously expressed in hematopoietic cells. One of the major roles of JAK2 is to trigger signal transduction following binding of the hematopoietic growth factor thrombopoietin (TPO), to its receptor c-Mpl, which initiates megakaryopoiesis. Previous findings focused on other hematopoietic growth factor receptors suggest that JAK2 is critical for translocation of the receptor to the membrane. Using hematopoietic cell lines, in which we transiently overexpressed human JAK2, we found that increased JAK2 expression had no effect on cell surface membrane localization. We also studied the effects of c-Mpl cell surface localization following over-expression of mutant forms of JAK2 (JAK2V617F and JAK2R564Q) which have been shown to cause myeloproliferative diseases in humans. Interestingly, contrary to previous reports, we found no difference in cell surface localization, following overexpression of mutant JAK2. Finally, we determined the effects of the JAK2R564Q mutation on cellular proliferation, survival, and signaling, comparing its effect to those of the more common JAK2V617F mutation. Although the JAK2R564Q mutation occurs within the same pseudokinase domain as JAK2V617F, the functionality of the mutations differs. Our results suggest that the JAK2R564Q mutation has the ability to prevent apoptosis while the JAKV617F contributes to hyperproliferation.