Grant: Project Grant

Proper regulation of genes is critical for health and disease. As the genetic material resides in the cell's nucleus, gene-regulating proteins should enter and leave the nucleus in a well-controlled manner. Two of these are called TAZ and YAP. They are similar to each other and play key roles in normal cell growth and development. However when they are not regulated properly, they induce serious diseases, including fibrosis (organ scarring) and cancer. A major gap in our knowledge is that we do not understand how these important proteins enter and leave the nucleus as they do not contain usual "postal codes" that directs them. We recently discovered a new nuclear postal code, present in TAZ/YAP and other cellular and viral proteins. However, we do not know how this ensures their nuclear entry. Moreover, recently two other regions were also implicated in TAZ/YAP nuclear import. However, we do not know how the various postal codes are regulated, and if they are sensitive to different stimuli (e.g. mechanical or chemical stress). Further, we identified a new drug that inhibits TAZ/YAP transport, but we do not know how it works. New data suggest that it stimulates TAZ/YAP egress from the nucleus. Finally, we found that our "postal code" functions not only in nuclear entry but may also regulate cell proliferation. Building on these exciting discoveries, and using sophisticated molecular and cell biology techniques, we will investigate: a) how TAZ/YAP enter the nucleus and how this process is regulated; b) how their nuclear export is regulated and modified by drugs, and if it could serve anti-cancer therapy; and c) how TAZ/YAP regulates cell proliferation. These studies will identify key new mechanisms in the cell biology of TAZ and YAP, including their nuclear traffic and role in proliferation. This knowledge is critical to develop potent tools and clinically effective drugs that can selectively interfere with their functions, and thus mitigate fibrosis and cancer.