An important aspect of neurofibromatosis research is to identify critical downstream effector pathways regulated by the NF1 and the NF2/Merlin tumor suppressor protein. Compared to NF1, the molecular function of the NF2/Merlin tumor suppressor protein is less well understood, which hampers the development of effective therapeutics against this devastating disease.

The fruit fly Drosophila has served as a powerful model system to investigate many evolutionarily conserved signaling pathways, due to its small size, short generation time, and the powerful genetic tools available in this system. Indeed, studies in Drosophila have provided critical insights into the function of numerous important human disease genes. Drosophila has a highly conserved NF2/Merlin gene, which like its mammalian counterpart, functions as a tumor suppressor gene by negatively regulating tissue growth. The NF2/Merlin genes in Drosophila and human are so similar that the human NF2/Merlin can substitute for the Drosophila NF2/Merlin gene in flies. The conserved tumor suppressor function from Drosophila to mammals suggests that studies of the Drosophila Merlin homologue may provide important insights into the molecular and cellular mechanisms of the NF2/Merlin tumor suppressor in humans.

Recently, my laboratory has identified a novel tumor suppressor gene in Drosophila named Kbr. Interestingly, we found that Kbr, NF2/Merlin, and the related FERM domain protein Expanded (Ex) form a protein complex. Furthermore, we found that the Kbr, Ex, NF2/Merlin (KEN) complex regulates the Hippo pathway, an emerging and evolutionarily conserved signaling pathway that controls tissue homeostasis from insects to mammals. The functional link between this newly discovered NF2/Merlin-containing protein complex and the Hippo pathway provides a potential mechanism through which NF2/Mer functions as a tumor suppressor protein.

The central goal of this application is to understand the molecular mechanism by which the KEN complex regulates the Hippo pathway, using both Drosophila and mammalian cells as model systems. Since the KEN complex was only recently identified, its molecular function has not been systematically studied before. Therefore, this application represents a new direction for NF2/Merlin research. The use of both Drosophila and mammalian cells makes this application highly relevant to understanding the molecular pathology underlying Neurofibromatosis Type II. The proposed studies will provide novel molecular insights into how NF2/Merlin functions as a tumor suppressor protein, which may lead to better prevention and treatment of Neurofibromatosis Type II. For example, a functional link between NF2/Merlin raises the exciting possibility that components of the Hippo pathway such as YAP may serve as potential drug targets for the treatment of Neurofibromatosis Type II. Thus, while the proposed studies are basic research in nature, these novel studies may lead to future impact on patient care.