Role of the STK Receptor in Erythropoiesis

正常的组织氧合需要红细胞的持续产生。 然而，稳态红细胞生成仅代表成人骨髓红细胞生成能力的一小部分，缺氧或急性贫血会引发骨髓和脾脏中红细胞生成的立即扩张。 此外，胎儿发育期间的造血主要是红细胞生成，这是由于需要满足生长中的胎儿的氧合要求。 在小鼠中，友伴红白血病病毒引起以急性红细胞增多症为特征的白血病，所述急性红细胞增多症发展为红白血病。最近，我们已经表明，一个自然发生的N-末端截短的Stk受体酪氨酸激酶是必不可少的朋友病毒感染的细胞的初始红细胞增多的扩张。 这些结果推进了Stk与Friend病毒包膜蛋白gp 55和Epo受体合作促进快速红细胞生成的假设。 STK编码FV-2的观察结果，加上来自我们实验室的初步数据，表明在MSP存在下增强的Epo依赖性集落形成和STK缺陷小鼠中响应于苯肼诱导的贫血的BFU-E扩增减少，表明MSP/STK在正常生理条件下调节红细胞生成中的作用，其中需要快速红细胞生成。 我们认为MSP/STK促进红细胞生成的能力依赖于其与Epo受体相互作用并促进信号传导的能力。 在该提议中，我们将检验以下假设：STK受体与Epo受体合作调节红系祖细胞对1）Epo刺激、2）Friend病毒感染和3）红细胞生成应激的反应。 在更大的背景下，所提出的研究应该促进对Epo受体介导的信号转导的理解，并且应该扩展我们对正常造血和白血病期间整合的I型细胞因子受体和受体酪氨酸激酶信号传导事件的基本知识。

Normal tissue oxygenation requires the continual production erythrocytes. However, steady-state erythropoiesis represents only a fraction of the erythroid capacity of adult bone marrow and hypoxia or acute anemia triggers an immediate expansion of erythropoiesis in the bone marrow and spleen. In addition, hematopoiesis during fetal development is primarily erythropoiesis due to the need to meet the oxygenation requirements of the growing fetus. In mice, friend erythroleukemia virus causes a leukemia that is characterized by an acute polycythemia which progresses to erythroleukemia. Recently, we have shown that a naturally occurring N-terminal truncation of the Stk receptor tyrosine kinase is essential for the initial polycythemic expansion of Friend virus infected cells. These results advance the hypothesis that Stk cooperated with Friend virus envelope protein gp55 and the Epo receptor to promote rapid erythropoiesis. The observation the STK encodes FV-2, coupled with preliminary data from our laboratory demonstrating enhanced Epo-dependent colony formation in the presence of MSP and decreased expansion of BFU-E in the STK- deficient mice in response to phenylhydrazine-induced anemia, suggest a role for MSP/STK in the regulation of erythropoiesis under normal physiological conditions where rapid erythropoiesis is required. We suggest that the ability to MSP/STK to promote erythropoiesis is dependent upon it's ability to interact with the Epo receptor and facilitate signaling. In this proposal we will test the hypothesis that the STK receptor cooperates with the Epo receptor to regulate the response of erythroid progenitors to 1) stimulation with Epo, 2) infection with Friend virus and 3) erythropoietic stress. In a larger context, the proposed studies should advance an understanding of Epo receptor- mediated signal transduction and should extend our basic knowledge of integrated type I cytokine receptor and receptor tyrosine kinase signaling events during normal hematopoiesis and leukemia.