The growth and biological effector function of cells in the immune and hematopoietic systems are tightly regulated by multiple extracellular factors, which include growth factors, cytokines, chemokine, antigens, and extracellular matrix proteins. Binding of these factor to their cognate receptors activates multiple downstream signaling cascades that result in immediate changes in cell behavior (release of mediators and cell migration), followed by changes in gene expression (cytokines) that ultimately change the cell state (proliferation and differentiation). Abnormal hyper-activation of receptor signal can result in diseases such as autoimmunity, leukemia , and allergy. Identification and characterization of novel key components downstream of receptors that regulate the growth and function of immune cells should provide new targets for therapeutic intervention. The long-term goal of this grant proposal is to understand the mechanism by which the novel scaffolding adapter Gab2/p97 regulates the biological responses of hematopoietic cells. Specifically, we will focus on defining the action of Gab2/p97 and Kit and FcepsilonRI (IgE receptor) signal transudations that respectively control the ontogeny and effector function of mast cell, the major cells involving in allergic responses. Gab2 belongs to the Dos/Gab subfamily of scaffolding adapters that also consists of Gab1 and Drosophila Dos. Dos and Gab1 have been implicated in various biological responses controlled by different receptors. Previous in vitro studies indicate that Gab2 plays an important role in cytokine and antigen receptor signaling in hematopoietic cells. Our recent studies using the Gab2 knockout mice that I generated reveal receptor signaling in hematopoietic cells. Our recent studies using the Gab2 knockout mice that I generated reveal Gab2 as an important molecule in mast cell effector function and development. Ga2-/- mice show decreased FcepsilonRI-evoked anaphylaxis and Gab-/- mast cells display defective FcepsilonRI-evoked biological responses in vitro. Therefore, we will define the detail mechanism of Gab2 action in FcepsilonRI signaling. Using molecular and biochemical approaches along with the Gab2-/- mice generated, we will examine how Gab2 is activated in response to FcepsilonRI activation. In addition, we will clarify how Gab2 regulates downstream components important for FcepsilonRI-evoked responses. Since Gab2-/- mice also show decreased tissue mast cell numbers, we will also investigate the role of Gab2 in Kit signaling that are known to regulate mast cell ontogeny. Using biochemical and genetic approaches, we will examine how Gab2 function as a new signaling pathway downstream of Kit. The outcome of this proposal will not only broaden our understanding in mast cell function and ontogeny at the molecular level but also may implicate that Gab2 and Ga2-associated or regulated molecules are potential targets for developing new drugs to treat allergy.
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