MOLECULAR MECHANISM OF ERYTHROID DIFFERENTIATION

我们研究了促红细胞生成素受体介导的红系细胞分化的分子机制。我们发现促红细胞生成素与受体的结合可诱导受体的酪氨酸磷酸化，酪氨酸磷酸化可诱导SH 2接头分子Shc和Grb 2与受体的结合，并通过Sos激活Ras，Raf-1、MAPKK和MAPK的磷酸化和激活，此外，我们还发现Vav和Tec激酶可被Epo刺激磷酸化，Vav通过Tec同源结构域与Tec结合。还发现JAK 2的活化不仅诱导STAT 5的活化，而且诱导STAT 1和STAT 3的活化，这反过来诱导STAT分子在特定靶基因中的特异性结合。在Epo刺激后，发现红细胞特异性转录因子NF-E2和加塔-1被激活，而这些因子也可以被血小板生成素激活，血小板生成素是调节巨核细胞-血小板形成的特异性细胞因子。加塔-1和NF-E2诱导红系细胞中的珠蛋白基因表达，同时它们刺激CD 61和其它血小板特异性抗原。我们还发现，没有酪氨酸磷酸化的受体，JAK-STAT途径可以被激活，并可以诱导细胞生长和crysthroid分化。

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.