Reversible phosphorylation of proteins on serine and threonine residues is a major mechanism for regulation of the activity, function, and/or localization of key proteins involved in most cellular processes. Whereas protein kinases that catalyze the forward reaction have been studied in great detail, less is known about the protein phosphatases responsible for the reverse reaction. The applicant's laboratory has had a long-standing interest in the study of the protein serine/threonine phosphatase 2A (PP2A) family of enzymes, which has been implicated in the control of many aspects of cellular signaling. Multiple regulatory mechanisms have been described for PP2A including post-translational modifications, association with phosphatase regulatory subunits, and interaction with specific cellular proteins. Recent published findings from the applicant's laboratory (Science 280:1258, 1998; J. Biol. Chem. 274:687, 1999) indicate that PP2A forms individual macromolecular complexes with several protein kinases, including Ca2+/calmodulin-dependent protein IV (CaMKIV) and p70 S6 kinase (p7OS6K). CaMKIV is predominantly expressed in the brain and T-lymphocytes, where it has been implicated in such processes as long-term potentiation and T cell activation, respectively. p7OS6K is a ubiquitous mitogen-activated kinase that plays a critical role in the regulation of protein synthesis. The applicant hypothesizes that the kinase-associated PP2A is a key modulator of the respective signaling pathway. To address this central hypothesis, the applicant proposes a series of complementary biochemical and molecular genetic investigations to determine: 1) the oligomeric composition of CaMKIV/PP2A and p7OS6K/PP2A complexes; 2) the role PP2A enzymes play in the control of CaMKIV and p7056K signaling; and 3) the mechanisms that regulate the assembly and function of the kinase/PP2A signaling complexes. These studies will provide fundamental mechanistic insights into the molecular biology of CaMKIV/PP2A and p7OS6K/PP2A signaling modules that will undoubtedly apply to other kinase/PP2A complexes. Given the importance of protein phosphorylation/dephosphorylation in the control of cell homeostasis, the proposed studies may also reveal novel therapeutic targets for diseases affecting normal cell growth and survival.
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