The regulation of hematopoietic lineages of cells is mediated, in part, by the function of a wide variety of cytokines that mediate their activities through structurally and functionally related receptors of the cytokine receptor superfamily. Research supported by this grant during the past funding periods has as its central goal the elucidation of the biochemical consequences of engagement of receptors of the cytokine receptor superfamily and the definition of the physiological consequences of the individual biochemical events. The focus of the studies have been with interleukin 3 (IL-3), a cytokine that affects cells of many stages of hematopoiesis but also has utilized receptors such as the receptor for erythropoietin (Epo). Past studies funded by this grant demonstrated the essential role that the Janus kinases (Jaks) play in cytokine receptor function. During the last granting period studies have focused on the role of receptor tyrosines and the biochemical events that are mediated by recruitment of signaling proteins by these tyrosines. Remarkably our studies with the Epo receptor demonstrate that in vivo erythropoiesis is largely unaffected by removal of a significant fraction of the cytoplasmic domain of the receptor and the elimination of all receptor tyrosines. These studies have therefore focused our attention on proteins recruited to the complex by phosphorylation of Jak2 and are substrates of Jak2. During the last granting period a number of signaling proteins were studies and their functions defined but none were critical for Epo or IL-3 signaling. The experiments proposed in this renewal application continue our efforts. In the first specific aim, we propose several strategies to identify substrates of Jak2 and approaches to establish their role in signaling. The second specific aim focuses on one critical pathway namely a Jak2-dependent pathway that is required for Bcl-X expression. Both genetic approaches and biochemical approaches are proposed to identify components of this pathway.
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