Role of the STK Receptor in Erythropoiesis

正常的组织氧合需要持续产生红细胞。然而，稳定状态的红细胞生成只占成人骨髓红系容量的一小部分，而缺氧或急性贫血会立即引发骨髓和脾中红细胞生成的扩大。此外，由于需要满足生长中胎儿的氧合要求，胎儿发育期间的造血主要是红细胞生成。在小鼠中，Friend红白血病病毒导致以急性红细胞增多症为特征的白血病，并进展为红白血病。最近，我们已经证明，自然发生的STK受体酪氨酸激酶的N端截断对于Friend病毒感染细胞最初的多核细胞扩增是必不可少的。这些结果提出了这样的假设，即STK与Friend病毒包膜蛋白gp55和EPO受体协同促进快速红细胞生成。对编码FV-2的STK的观察，再加上我们实验室的初步数据显示，在苯肼诱导的贫血反应中，STK缺陷小鼠的EPO依赖集落形成增加，BFU-E的扩张减少，这表明MSP/STK在正常生理条件下需要快速红细胞生成的红细胞生成调节中发挥作用。我们认为，MSP/STK促进红细胞生成的能力依赖于它与EPO受体相互作用并促进信号转导的能力。在这个方案中，我们将检验STK受体与EPO受体协同调节红系祖细胞对1)EPO刺激、2)Friend病毒感染和3)红系应激反应的假设。在更广泛的背景下，建议的研究将促进对EPO受体介导的信号转导的理解，并扩大我们对正常造血和白血病过程中整合的I型细胞因子受体和受体酪氨酸激酶信号转导事件的基本知识。

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.