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 activated by erythropoietin (EpO) and erythropoietin co-stimulatory factors (kit ligand), insulin-like growth factor, thrombopoietin, interleukin 3 and granulocyte-macrophage colony-stimulating factor) in normal human bone marrow CD34(+) cells and d 11 erythroid burst forming unit derived glycophorin+ cells. The activation of these signal transduction pathways was further correlated with various biological effects such as (i) cell proliferation, (ii) inhibition of apoptosis, (iii) activation of adhesion and (iv) secretion of the matrix metalloproteinases (MMPs) MMP-9 and MMP-2, and vascular endothelial growth factor (VEGF). We found that in human CD34(+) cells and erythroblasts 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 orchestrated activation of multiple signalling cascades. Accordingly, we found that although cell proliferation was more related to simultaneous activation of JAK-STAT and MAPK p42/44, the effect on cell survival correlated with activation of PI-3K-AKT, MAPK p42/44 and JAK-STAT proteins. We also demonstrated that differentiating normal human erythroid cells lose their adhesive properties 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 bone marrow.
Ratajczak
J
J
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Majka
M
M
Kijowski
J
J
Baj
M
M
Pan
Z K
ZK
Marquez
L A
LA
Janowska-Wieczorek
A
A
Ratajczak
M Z
MZ
D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism; D004789:Enzyme Activation; D015672:Erythroid Precursor Cells / Q000276:immunology / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D007377:Interleukin-3; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019089:Stem Cell Factor; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013926:Thrombopoietin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2