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 Epo