Neurofibromatosis: A New Model for Merlin Localization and Function

Posted February 11, 2005

Wallace Ip, Ph.D., University of Cincinnati College of Medicine, Ohio

NF2, an inherited disorder that affects 1 in 40,000 individuals, is characterized by the formation of bilateral schwannoma of the 8th cranial nerve and predisposition to other nervous system tumors. NF2 is caused by mutations in a tumor suppressor gene called merlin, a member of a family of proteins that bind to the structural support network in cells (known as the cytoskeleton). Recent work by Dr. Wallace Ip at the University of Cincinnati College of Medicine, a recipient of an FY02 NFRP Idea Award, provides new insight into merlin localization and function. Dr. Ip's group demonstrated that most merlin within cells is attached to specialized areas of the cell membrane called lipid rafts. His data also suggest that merlin activation is accompanied by dissociation of merlin-containing lipid rafts from the cytoskeleton. Merlin is the first tumor suppressor to be localized to lipid rafts, which contain a high concentration of signaling molecules that regulate cell growth. These findings suggest that the ability of merlin to disrupt growth-promoting signaling pathways originating from the cell membrane may be dependent on its association with the rafts. Future studies will examine whether mutant merlin proteins modeled after mutations known in NF2 patients are defective in lipid raft targeting and whether forced localization of the mutant proteins to lipid rafts can restore normal function. Dr. Ip's research may provide explanations for the loss of function associated with some merlin mutations and ultimately help investigators develop new therapeutics for the affected individuals.

Publications:

Stickney JT, Bacon WC, Rojas M, et al. 2004. Activation of the tumor suppressor merlin modulates its interaction with lipid rafts. Cancer Research 64:2717-2724.