NERVE GROWTH FACTOR SIGNALING

Auburn University At Auburn, Auburn University AL

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Abstract

DESCRIPTION (Adapted from applicant's abstract): Atypical PKC isoforms (iota/zeta) have been shown to play a critical role in regulation of various neuronal processes including, differentiation, survival and long-term potentiation. In PC-12 cells a PKCs, as well as their second messenger activator, P13 polyphosphoinositides, are required for both differentiation and survival responses. We have recently shown that aPKCs are tyrosine phosphorylated in response to nerve growth factor (NGF). ZIP/p62 and Par4 are binding proteins that regulate the localization and activation of aPKCs. Preliminary studies document an NGF receptor-regulated phosphotyrosine dependent interaction of src with sPKC. We hypothesize that tyrosine phosphorylation of atypical PKC by src moduates activity, as well as, its ability to interact with its protein regulators, Par4 and ZIP. Therefore, one specific aim is to study the mechanisms by which aPKC-iota is regulated by tyrosine phsophorylation to include regulation by NGF receptor components, p75 and TrkA, as well as, second messenger. A second aim is to unravel the mechanismwhereby aPKC is regulated by src kinase to include regulation of aPKC localization, signal-complex formation and interaction with protein regulators, as well as to examine the specific tyrosine residues that regulate NGF/aPKC signal-coupling. Various biochemical and functional assays will be used to define the function of src in regulation of aPKC signaling. Overall, a comprehensive set of experiments using enzyme activity assays, subcellular fractionation, coimmunoprecipitation and site-directed mutagenesis will be employed. The outcome of this work will continue to alter the conceptual framework of neurotrophic signal coupling and the role that aPKC plays in this process. These findings will contribute to further understanding of the mechanism whereby aPKC is regulated and may provide new therapeutic targets for neurodegenerative disorders.