Cytoplasmic and transcriptional control of Hippo signaling

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Project Summary/Abstract The overall goal of this proposal is to understand how organisms as diverse as humans and the fruit flies use the same molecules to determine how large their organs will grow. The specific focus of this application is a protein that controls expression of genes that in turn encode for proteins that promote growth. In flies this `pro- growth' factor is called Yorkie and in our cells it is called Yap1, however it performs the same job in both species. When Yorkie/Yap1 is `active' in cells, it tells the cells to grow and divide, and thus generates many new cells. This makes tissues larger since they have more cells, but it can also lead to the growth of a cancerous tumor. We know a bit about how Yorkie/Yap1 become `active' but not enough to reliably predict when and where this happens, or how it promotes cancer when it becomes `active' all the time. We have found three other proteins that physically bind to Yorkie: RhoGAP15B, Taiman, and Bonus, and we think they may be key to understanding when and where Yorkie gets activated. RhoGAP15B has the ability to bind cell membranes, so we hypothesize that it may interact with Yorkie and tether it to specific kinds of membranes in epithelial cells. Yorkie is known to localize to a set of membranes in the cellular cytoplasm called `endosomes', and RhoGAP15B may be the factor that takes it there. Taiman and Bonus are proteins that are found in the nucleus, where the DNA is housed, and get `activated' by the fly equivalent of the human sex hormones estrogen and testosterone. We think that when these hormones `activate' Taiman and Bonus that they also activate Yorkie, and that this is an important way cells receive signals to turn `on' genes in the DNA that tell the cells to grow and divide. Our experiments will address each of these ideas: Does RhoGAP15B help tether Yorkie to cell membrane and why does this matter? Do Taiman and Yorkie cooperate in binding to DNA and selecting which genes get expressed from the DNA in the nucleus? Is Bonus involved in helping Yorkie activate genes that are responsible for cell growth and division? Although we use flies to study these ideas, we remain confident that much of what we learn will teach us about how all of the proteins work in our cells.