Search for Insulin Secretion Modulators, Novel Functions of WNK Signaling and Intramolecular Signal Transduction in ERK2

In this dissertation, the regulation of insulin secretion from pancreatic beta cells, WNK1 pathway involvement in cell migration, angiogenesis, breast cancer, and other processes, as well as ERK2 intradomain communication are discussed. Each chapter is dedicated to a separate project, but the common denominators for these projects are protein kinases involved in the WNK or ERK pathway. Through an assay developed in the lab to detect compounds that have an extended action on insulin secretion, novel insulin secretion modulators were discovered. Using a bioinformatics platform, previously unknown downstream effectors of the WNK pathway were identified. Depletion of WNK1 in endothelial cells and breast cancers further defined WNK1-sensitive processes involved in cell migration and metastasis of breast cancer. Finally, ERK2 mutants were characterized to explore allosteric regulation between substrate binding sites and the ERK activation mechanism.