REGULATION OF G PROTEIN SIGNALING

Duke University, Durham NC

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Abstract

A vast number of signaling systems have been shown to be regulated by heterotrimeric guanine nucleotide binding regulatory proteins (G proteins). Cellular processes controlled through G protein action including hormone, neurotransmitter and growth factor action, and these proteins have also been implicated in intracellular membrane trafficking and secretion. The broad goal of the research proposed in this application is to understand the molecular mechanisms of how specific members of the G protein family function in specific cellular signaling pathways. The proposed research centers on elucidating the signaling pathway(s) controlled by one such member, termed GZ. GZ is a G protein predominately found in neuroendocrine tissues that has been linked, among other things, to control of cyclic nucleotide levels in these tissues. GZ contains unique structural features that result in properties that distinguish it from most other characterized G proteins, including a very slow intrinsic rate of GTP hydrolysis toxin and the capacity to be regulated by direct phosphorylation mediated by protein kinase C. An interaction cloning strategy that has recently been completed has resulted in the identification of four proteins that interact with GZ. Three of the identified GZ-interacting proteins can be directly implicated in cellular signaling processes, while the fourth is the product of a recently-identified gene homologous to a Drosophila gene whose function is unknown but which has been implicated in eye development in this organism. We will employ a variety of biochemical, molecular, and cellular techniques to study these four proteins in a concerted effort to ascertain the functional consequences of their interaction with GZ and to elucidate potential involvement in GZ- mediated signaling processes.