|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1995 : ¥1,800,000 (Direct Cost : ¥1,800,000)
We have studied the molecular mechanism of erythropoietin receptor-mediated erythroid cell differentiation. We found that the binding of erythropoietin to the receptor induces the tyrosine-phosphorylation of the receptor, which in turen induces the binding of SH2 adaptor molecules Shc and Grb2 to the receptor, activation of Ras through Sos, phosphorylation and activation of Raf-1, MAPKK and MAPK.Furthermore, we found that Vav and Tec kinase can be phosphorylated by Epo stimulation and that Vav binds to Tec through Tec homology domain. It was also found that the activation of JAK2 induces activation of not only STAT5 but also STAT1 and STAT3, which in turn induces the specific binding of the STAT molecules in the specific target genes. After Epo stimulation, erythroid-specific transcription factors NF-E2 and GATA-1 were found to be activated, while these factors can be also activated by thrombopoietin, which is a specific cytokine regulating megakaryocyte-platelet formation. The GATA-1 and NF-E2 induces globin gene expression in erythroid cells, while they stimulate CD61 and other platelet-specific antigens. We also found that without tyrosine-phosphorylation of the receptor, JAK-STAT pathway can be activated, and both cell growth and crythroid differentiation can be induced.