Protein Phosphatases in Lymphocyte Signal Transduction

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DESCRIPTION (provided by applicant): INK and NF-kappaB are involved in T-cell activation/differentiation, inflammatory responses, apoptosis, and cell proliferation. Protein phosphatase 4 (PP4) is an okadaic acid-sensitive protein serine/threonine phosphatase. To date, little is known about the functions of PP4. Our results provide the first evidence for the existence of PP4/JNK and PP4/ NF-kappaB modules as a new paradigm for the control of the signaling pathways in T cells. Understanding the underlying mechanisms of PP4-mediated T-cell signal transduction will lead to the discovery of the functions of PP4. This application plans to study the roles of PP4 in T-cell signaling and T-cell mediated immune responses. To unveil novel physiological functions of PP4 in T cells, we will generate PP4 knockout cells and mice using the Cre-foxP recombination system and Lck-Cre transgenic mice. The approaches are: (i) to understand the roles PP4 in T-cell proliferation, apoptosis, differentiation, centrosome function, and signaling using various biochemical and genetic approaches, and (ii) to study the in vivo functions of PP4 in Th1/Th2 differentiation, immune responses, and autoirnmunity. Ultimately, we plan to dissect various PP4-mediated signaling pathways in immune responses, leukemia/lymphoma, and immunological diseases. Our future understanding of host factors involved in the PP4-mediated lymphocyte signaling pathways will provide information fundamental to the discovery, design, and evaluation of effective intracellular therapeutic agents for leukemia/lymphoma, infections, and immunological disorders such as autoimmunity. The specific aims are: Aim 1. Study the roles of PP4 in T-cell proliferation, apoptosis, differentiation, and signaling using PP4 conditional knockout mice and cells. Aim 2. Study in vivo functions of PP4 in T-cell mediated immune responses and autoimmunity using Tcell specific PP4 conditional knockout mice.