Membrane distribution of the NF2 tumor suppressor, Merlin

Neurofibromatosis type 2 (NF2) is a familial cancer syndrome that affects approximately 1 in 40,000 individuals, resulting in slow growing benign tumors of the nervous system. NF2 develops following the inheritance of one mutant allele of the NF2 gene and subsequent somatic loss or inactivation of the remaining wild-type allele. Analysis of the NF2 gene product, Merlin, reveals that it exhibits high homology to a group of proteins that include Ezrin, Radixin, and Moesin (ERM proteins). The ERM proteins provide regulatable linkage of the membrane to the cytoskeleton to direct cellular remodeling processes. The similarities between Merlin and the ERM proteins suggest that Merlin functions at the membrane:cytoskeleton interface, a novel site for tumor suppressor activity.Understanding the mechanism of action of any tumor suppressor requires a detailed understanding of its subcellular distribution. Indeed, membrane localization of Merlin is critical for as tumor suppressor activity. Here I demonstrate that Merlin residues 1-18 direct Merlin to a precise subcellular insoluble membrane compartment whereby it can interact with various membrane-associated proteins to regulate cellular growth. Furthermore, I identify additional putative phosphorylation sites on Merlin that may be critical in regulating the tumor suppressor activity of Merlin. Finally, I describe a conditionally activatable allele for the murine Nf2 gene that will allow controlled Merlin expression in a highly regulated manner. This will permit examination of the consequences of endogenous Merlin reintroduction in an Nf2 -/- background and provide a valuable tool for extending the studies described in this thesis.