Structure and Signal Transduction of the Erythropoietin Receptor

促红细胞生成素(EPO)与其膜受体相互作用可诱导红系祖细胞增殖和分化。EPO受体介导的信号转导的分子机制尚不清楚，因为克隆的EPO受体在其胞浆区域不包含任何酶相关或核苷酸结合的共有序列。我们已经证明，携带EGF受体的胞外区与EPO受体的胞内区相连的嵌合受体可以在白介素3依赖的BA/F3细胞系中传递EGF依赖的增殖信号，支持EPOR通过受体二聚化而激活的假说。我们还发现，这些嵌合受体可以在EPO反应性红白血病细胞系TSA8中传递红系分化信号。EGF和EPO诱导表达嵌合受体的TSA8细胞合成珠蛋白和血红蛋白。携带EGF受体胞外区和EPOR胞浆区约120个氨基酸残基的嵌合受体也可以在BA/F3细胞中传递增殖信号，在TSA8细胞中传递分化信号。这些数据表明，如果EPOR的细胞质结构域被二聚化适当地激活，它就足以产生增殖和分化信号。我们克隆了EPO诱导的即刻早期基因CIS，该基因含有SH2结构域。EPO的诱导机制和CIS的作用目前正在研究中。

Interaction of erythropoietin (EPO) and its memebrane receptor induces the proliferation and differentiation of erythroid progenitors. The molecular mechanism of the EPO receptor-mediated signal transduction remains unclear because the cloned EPO receptor does not contain any enzyme-related or nucleotide-binding consensus sequences in its cytoplasmic domain. We have shown that chimeric receptors carrying the extracellular domain of the EGF receptor linked to the cytoplasmic domain of the EPO receptor can transmit EGF dependent-proliferation signals in an interleukin-3 dependent Ba/F3 cell line, supporting the hyphothesis that the EPOR is activated by receptor dimerization. We also showed that these chimeric receptors can transmit erythroid differentiation signals in an EPO-responsive erythroleukemia cell line, TSA8. EGF as well as EPO induced globin and hemoglobin synthesis in TSA8 cells expressing the chimeric receptor. A chimeric receptor carring the extracellular domain of the EGF receptor and the membrane proximal about 120 amino acids of the cytoplasmic domain of the EPOR can also transmit proliferation in Ba/F3 cells and differentiation signals in TSA8 cells. These data indicate that a membrane proximal region the cytoplasmic domain of the EPOR is sufficient to produce both proliferation and differentiation signals if it is properly activated by dimerization. We isolated and EPO-induced immediate early gene, CIS which contains SH2 domain. Mechanism of the induction by EPO and function of CIS is now under investigation.