Endocrine disease in the United States is increasing at an alarming rate. Approximately 40 million people are currently debilitated by diabetes, hypothyroidism, or infertility alone and the incidence of these and other endocrine diseases is expected to increase. Although this broad collection of diseases has many causes, these numbers nonetheless underscore the importance of endocrine and neuroendocrine homeostasis for our health. This homeostasis relies on the ability of stimulus-triggered secretory cells to correctly sort, package, and process numerous molecules either into or away from the maturing secretory granules. The cellular mechanisms that control the sorting of these molecules, however, are poorly understood. Both the trans-Golgi network and the immature granules are key sorting stations for the formation of dense-core, stimulus- triggered secretory granules. The immature granule functions as a """"""""gatekeeper"""""""" that segregates a collection of seemingly unrelated """"""""TGN/endosomal"""""""" membrane proteins from those destined for inclusion in mature granules. Retrieval of these non-granule membrane proteins requires an acidic cluster sorting signal that must be phosphorylated by casein kinase 2. Recently, my laboratory reported the identification of a novel cell sorting protein, named PACS-1, that binds to these phosphorylated acidic cluster signals and is required for the retrieval of the non- granule membrane proteins from the immature granule. Our identification of PACS-1 has provided new insights into secretory granule formation. The proposed studies will first determine the biochemical bases for the binding of PACS-1 to these phosphorylated acidic-cluster sorting motifs and how PACS-1 sorting activity itself is regulated by phosphorylation. Second, we will determine the subcellular localization of PACS-1 and the mechanism by which it is recruited to immature granules. Third, we will determine the importance of PACS-1 to neuroendocrine cell physiology. Together, these studies will improve our understanding of the regulation of protein sorting in neuroendocrine cells, as well as increase our knowledge of the cell biology underlying both endocrine and neuroendocrine homeostasis.
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