Protein Phosphatases and Proinflammatory Cytokines

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DESCRIPTION (provided by applicant): Protein phosphatase 4 (PP4) is a protein phosphatase 2A (PP2A)-related serine/threonine phosphatase. PP2A is involved in regulating diverse cellular processes such as cell signaling, cell cycle regulation, apoptosis, and tumorigenesis; however, little is known about the functions of PP4. Many of the above functions identified for PP2A were based on the studies using okadaic acid, an inhibitor previously thought to be PP2A-specific, but now known to inhibit PP4 at similar concentrations. Therefore, some of the previously identified functions assigned to PP2A may in fact be the functions for PP4. PP4 binds to and activates Rel/NF-KB proteins. Rel/NF-KB proteins are pivotal molecules that are involved in a plethora of cellular responses such as gene regulation, apoptosis, cell cycle, cell proliferation, oncogenesis, inflammation, and cell adhesion/migration. Our recent results also indicate that PP4 activates cJun N-terminal kinase (JNK). JNK subgroup belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK kinase cascade is involved in apoptosis, differentiation, cell proliferation, oncogenesis, and various stress responses such as inflammatory responses and heart ischemia/reperfusion. Understanding the functions and regulation of PP4, as well as the underlying mechanisms of NF-KB/JNK activation by PP4 will lead to a better understanding of the NF-KB, JNK and PP4 signaling pathways. The specific aims are the following: (1) to study the regulation andfunction of PP4, (2) to determine the role of PP4 in NF-KB activation, and (3) to determine the role of PP4 in JNK activation, The information derived from this study should provide important information for a better design of therapeutic drugs for inflammatory diseases, cancers, and cardiac diseases.