STRUCTURAL-ANALYSIS OF DROSOPHILA MERLIN REVEALS FUNCTIONAL DOMAINS IMPORTANT FOR GROWTH-CONTROL AND SUBCELLULAR-LOCALIZATION

Merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppre ssor gene, is a member of the protein 4.1 superfamily that is most clo sely related to ezrin, radixin, and moesin (ERM), NF2 is a dominantly inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumors associated with the central nervo us system. To understand its cellular functions, we are studying a Mer lin homologue in Drosophila. As is the case for NF2 tumors, Drosophila cells lacking Merlin function overproliferate relative to their neigh bors. Using in vitro mutagenesis, we define functional domains within Merlin required for proper subcellular localization and for genetic re scue of lethal Merlin alleles. Remarkably, the se results of these exp eriments demonstrate that all essential genetic functions reside in th e plasma membrane-associated NH2-terminal 350 amino acids of Merlin, R emoval of a seven-amino acid conserved sequence within this domain res ults in a dominant-negative form of Merlin that is stably associated w ith the plasma membrane and causes overproliferation when expressed ec topically in the wing. In addition, we provide evidence that the COOH- terminal region of Merlin has a negative regulatory role, as has been shown for ERM proteins. These results provide insights into the functi ons and functional organization of a novel tumor suppressor gene.