Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3

• Published in: Blood Vol. 89; no. 8; pp. 2664 - 2669
• Main Authors: NAGATA, Y, NISHIDA, E, TODOKORO, K
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 15.04.1997
• Subjects: Animals; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Enzyme Activation - drug effects; Erythropoietin - pharmacology; Fundamental and applied biological sciences. Psychology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Interleukin-3 - pharmacology; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mice; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Molecular and cellular biology; Phosphorylation; Protein Kinases - metabolism; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; Signal Transduction - drug effects; Thrombopoietin - pharmacology; Erythropoietin; Enzyme; Transferases; Stem cell; Cytokine; Rodentia; Hematopoietic cell; Activation; Glycoprotein hormone; Thrombopoietin; Signal transduction; Vertebrata; Mammalia; Mouse; Hematopoiesis; Interleukin 3; Kinase; Animal; C-Onc gene; Mitogen; Protooncogene; Growth factor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v89.8.2664

A variety of environmental stresses, such as osmotic shock, UV radiation, and heat shock, or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 reportedly induce activation of c-Jun amino-terminal kinases (JNK), which are usually activated by SEK1/MKK4. We report here that the hematopoietic cytokines interleukin-3 (IL-3), erythropoietin (Epo), and thrombopoietin (Tpo), which regulate growth and 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 progenitor cells. However, immunoblot analysis and in vitro kinase assay showed that neither phosphorylation nor activation of SEK1/MKK4 was induced by IL-3, Epo, or Tpo stimulation. Therefore, we concluded that the JNK signaling cascade plays an important role not only in stress responses and proinflammatory cytokine actions but also in hematopoietic cytokine actions and that hematopoietic cytokines may activate the JNKs through a kinase other than SEK1/MKK4, as previously suggested for stress-activated cells.