Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells

The aim of this study was to identify signal transduction pathways activate d by erythropoietin (EpO) and erythropoietin co-stimulatory factors (kit li gand), insulin-like growth factor, thrombopoietin, interleukin 3 and granul ocyte-macrophage colony-stimulating factor) in normal human bone marrow CD3 4(+) cells and d 11 erythroid burst forming unit derived glycophorin(+) cel ls. The activation of these signal transduction pathways was further correl ated with various biological effects such as (i) cell proliferation, (ii) i nhibition of apoptosis, (iii) activation of adhesion and (iv) secretion of the matrix metalloproteinases (MMPs) MMP-9 and MMP-2, and vascular endothel ial growth factor (VEGF). We found that in human CD34(+) cells and erythrob lasts erythropoietic factors may activate similar but different signalling pathways, and that activation of each of the JAK-STAT, MAPK p42/44 or PI-3K -AKT axes alone is not sufficient either to stimulate cell proliferation or inhibit apoptosis, suggesting that these processes are regulated by orches trated activation of multiple signalling cascades. Accordingly, we found th at although cell proliferation was more related to simultaneous activation of JAK-STAT and MAPK p42/44, the effect on cell survival correlated with ac tivation of PI-3K-AKT, MAPK p42/44 and JAK-STAT proteins. We also demonstra ted that differentiating normal human erythroid cells lose their adhesive p roperties and secrete angiopoietic factors such as MMP-9, MMP-2 and VEGF,(- ) and we postulate that this secretion by early erythroid cells may play a role in their maturation and egress from the haematopoietic niches of the b one marrow.