J. Ratajczak et al., Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells, BR J HAEM, 115(1), 2001, pp. 195-204
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.