Neurofibromatosis 2 (NF2) is an inherited disease characterized by the formation of brain and spinal tumors called schwannomas. As the brain tumors enlarge, they can compress cranial nerves and adjacent brain structures resulting in deafness, dysequilibrium or other neurologic problems. NF2 is a tumor suppressor since its inactivation leads to tumor formation. NF2 bears homology to a growing family of proteins called the ERM family which play a role in linking the plasma membrane to the cytoskeleton. However, despite structural similarities with ERM proteins, the cellular functions of NF2 are unknown. Our lab has shown that cells from primary human schwannomas exhibit abnormal membrane ruffling and stress fiber formation on binding to matrix. We hypothesize that NF2 mutation results in actin disorganization which contributes to tumor formation. To determine how NF2 functions at the molecular and cellular level, I propose to: 1) Rescue the schwannoma phenotype using full length NF2 protein, after learning how to express NF2 transgenes in human schwannoma cells; 2) Identify relevant NF2 domains, by constructing and expressing deletion mutants; 3) Place NF2 in small GTPase signaling cascades by using activated and dominant negative forms of Rho, Rac and Ras in primary schwannoma cells.
| Bashour, Anne-Marie; Meng, J-J; Ip, Wallace et al. (2002) The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. Mol Cell Biol 22:1150-7 |
| Meng, J J; Lowrie, D J; Sun, H et al. (2000) Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin. J Neurosci Res 62:491-502 |
