Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology. Classical cadherins are cell-cell adhesion proteins that regulate tissue morphogenesis and cell junctions during physiological processes. They are highly regulated at the cell surface, controlling dynamic interactions between cells. Although much is known about the basic functions of cadherin-mediated adhesion, an understanding of the mechanisms underlying dynamic cell surface regulation, has not yet been achieved, nor is it well understood how such regulatory mechanism control physiological processes in vivo. Cadherins also transduce signals into the cell to convey information about the state of the tissue. One way they do is by stimulation of the Hippo-YAP signaling pathway to mediate contact inhibition of growth. This process is antagonized by growth factor signaling, via the PI3-kinase (PI3K) signaling pathway, which inhibits the Hippo pathway and stimulates nuclear YAP. We will investigate the mechanisms underlying the regulation of cadherin homophilic adhesive binding at different levels of analysis, from basic biochemical/biophysical/structural mechanisms, through cell biological process controlling adhesion (especially the role of p120-catenin), to evaluating the roles of adhesion regulation in physiological processes in vivo. We've found that cancer- and cleft lip-associated mutations in E- cadherin specifically interfere with the regulation of adhesion at the cell surface, and these will provide valuable tools for these studies. In vivo studies of cadherin regulation will focus on their roles in physiological control of barrier function in both epithelia and endothelia, especially during inflammatory processes where control of these functions are especially important. Studies on endothelial junctional regulation will require us to develop tools for studying VE-cadherin regulation, including activating antibodies, and models for endothelial barrier function; these will be compared to our studies of E-cadherin in epithelia. We'll also investigate the mechanisms by which cadherins transduce various signals into the cell. A major focus will be on the regulation of the Hippo-YAP pathway and associated TEAD transcription factors by cadherin-mediated contact and by growth factors and PI3K signaling. The goals are both to understand how they function and to enable us to develop genetic approaches to selectively perturb these interactions in vivo to evaluate their importance. Hippo signaling by formation of cadherin contacts will be compared to signaling by tight junctions as well as signals produced by mechanical tension at the cadherins. The Hippo-YAP pathway may be an important new branch of the PI3K signaling pathway that regulates tissue growth in addition to the well-known Akt-TOR pathways. This hypothesis will be tested in vivo both by studies on tissue overgrowth diseases caused by somatic mosaic constitutively active PI3K mutations and by studies of mouse models of mammary tumorigenesis. This project should reveal how cadherins work as bidirectional signaling proteins to transduce changes across the membrane and how these processes regulate the physiology and growth of tissues and organs in vivo.
Cadherins are proteins on the cell surface that work in association with proteins inside the cell called catenins to assemble cells properly into tissues during development, maintain tissue structure and organization in organs, and control the permeability barriers of tissues that line organs and blood vessels. They also communicate the state of cell contact into the cell in order to control organ growth and development. This project will analyze how cadherins and associated proteins control these processes in normal and diseased tissues.