ACTIVATION OF JNK SIGNALING PATHWAY BY ERYTHROPOIETIN, THROMBOPOIETIN, AND INTERLEUKIN-3

A variety of environmental stresses, such as osmotic shock, UV radiati on, and heat shock, or the proinflammatory cytokines tumor necrosis fa ctor-alpha and interleukin-1 reportedly induce activation of c-Jun ami no-terminal kinases (JNK), which are usually activated by SEK1/MKK4. W e report here that the hematopoietic cytokines interleukin-3 (IL-3), e rythropoietin (Epo), and thrombopoietin (Tpo), which regulate growth a nd differentiation of hematopoietic progenitor cells, erythroids, and megakaryocytes/platelets, respectively, also activate a JNK signaling cascade. In-gel kinase assay as well as in vitro kinase assay clearly showed that IL-3, Epo, and Tpo rapidly and transiently activated both JNK1 and JNK2 in IL-3-, Epo-, or Tpo-dependent mouse hematopoietic pro genitor cells, However, immunoblot analysis and in vitro kinase assay showed that neither phosphorylation nor activation of SEK1/MKK4 was in duced by IL-3, Epo, or Tpo stimulation, Therefore, we concluded that t he JNK signaling cascade plays an important role not only in stress re sponses and proinflammatory cytokine actions but also in hematopoietic cytokine actions and that hematopoietic cytokines may activate the JN Ks through a kinase other than SEK1/MKK4, as previously suggested for stress-activated cells. (C) 1997 by The American Society of Hematology .