The Hippo signaling pathway is an evolutionarily conserved mechanism that controls organ size in animals. Pathway output is mediated by Yorkie, a transcriptional co-activator that positively regulates transcription of genes that promote tissue growth. In addition, Yorkie and its mammalian ortholog YAP have been observed to localize to the cell cortex and there is growing evidence that they may have cytoplasmic functions that are independent of their nuclear functions as transcriptional coactivators. In this dissertation I explore potential functions of Yorkie at the cell cortex. I first identify a novel function of Yorkie to promote activation of myosin at the cell cortex through a myosin regulatory light chain kinase, Stretchin-Mlck. This Yorkie function is not dependent on its transcriptional activity and is required for larval and adult tissues to achieve appropriate size. Recent studies have shown that cytoskeletal tension can activate both Yorkie and YAP, resulting in increased nuclear localization and tissue growth. Therefore, I propose that Yorkie functions in a feed-forward ‘amplifier’ loop that promotes myosin activation, and thereby greater Yorkie activity, in response to tension. Many of the Hippo pathway components and regulators concentrate at the cell cortex where apical polarity proteins reside. In this dissertation I find a possible role for Yorkie in organizing Hippo pathway components at the cell cortex. I also further analyze the functional interactions between the Hippo pathway and apical polarity proteins and identify two apical polarity proteins Bazooka and atypical protein kinase C as potential positive regulators of the Hippo pathway. Together, the findings described in this dissertation provide new insights into the regulation of the Hippo pathway and point to new directions for future studies of this fascinating signaling pathway.




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