The ability of epithelial cells to alter their morphology, move, and assume new cell-cell and cell-matrix interactions is a critical aspect of their function both during organ development and in the responses of the adult organism to injury. During development, these events are central to the outgrowth and branching of structures such as the ureteric bud as it forms the collecting system of the kidney and the epithelial bud of the lung as it forms the bronchial tree. In the adult, injury to the kidney results in a reversal of this process with de-differentiation of the surviving epithelia into a more mesenchymal phenotype, which must then undergo growth factor mediated cell spreading, migration, and proliferation to successfully regenerate a functional tubule. Due to the central nature of cell shape change in both of these processes, our laboratory has focused its research efforts on understanding how growth factors can mediate cell morphogenesis. The results of this work have led us to an understanding that activation of the ERK/MAPK signaling pathway plays a fundamental role in the regulation of cell morphogenesis by several growth factors, and has resulted in our discovery that paxillin, a protein in the focal adhesion complex that is critical for the turnover of sites of contact between the cell and its matrix, is associating with, and phosphorylated by, the Raf/MEK/ERK members of the MAPK pathway. We believe that this association underlies a novel role for paxillin as a scaffold to selectively facilitate MAPK signaling at the focal adhesion complex. Exploration of the mechanism of this scaffolding effect is of particular importance because it addresses the fundamental question of how the effects of a signaling pathway (such as MAPK) that is activated by multiple different stimuli can still be insulated in such a way as to ultimately regulate specific cellular targets under specific conditions. This will be undertaken by first identifying the role of paxillin as a scaffold for MAPK activation in the cell (SA 1), then determining the events that ERK regulates at the focal adhesion (SA 2), and finally exploring the importance of these events in both single cell morphogenesis as well as multicellular organogenesis during development (SA 3).
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