Role of the STK Receptor in Erythropoiesis

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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.