Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors

• Published in: Blood 2004-06, Vol.103 (12), p.4457-4465
• Main Authors: van den Akker, Emile, van Dijk, Thamar, Parren-van Amelsvoort, Martine, Grossmann, Katja S., Schaeper, Ute, Toney-Earley, Kenya, Waltz, Susan E., Löwenberg, Bob, von Lindern, Marieke
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Chlorocebus aethiops; Erythropoietin - pharmacology; Fundamental and applied biological sciences. Psychology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hemoglobins - metabolism; Humans; Janus Kinase 2; Molecular and cellular biology; Phosphoproteins - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins; Rabbits; Receptor Protein-Tyrosine Kinases - physiology; Receptors, Erythropoietin - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-08-2713

Erythropoietin (EPO) is required for cell survival during differentiation and for progenitor expansion during stress erythropoiesis. Although signaling pathways may couple directly to docking sites on the EPO receptor (EpoR), additional docking molecules expand the signaling platform of the receptor. We studied the roles of the docking molecules Grb2-associated binder-1 (Gab1) and Gab2 in EPO-induced signal transduction and erythropoiesis. Inhibitors of phosphatidylinositide 3-kinase and Src kinases suppressed EPO-dependent phosphorylation of Gab2. In contrast, Gab1 activation depends on recruitment and phosphorylation by the tyrosine kinase receptor RON, with which it is constitutively associated. RON activation induces the phosphorylation of Gab1, mitogen-activated protein kinase (MAPK), and protein kinase B (PKB) but not of signal transducer and activator of transcription 5 (Stat5). RON activation was sufficient to replace EPO in progenitor expansion but not in differentiation. In conclusion, we elucidated a novel mechanism specifically involved in the expansion of erythroblasts involving RON as a downstream target of the EpoR. (Blood. 2004;103:4457-4465)