AN ANTI-RAS FUNCTION OF NEUROFIBROMATOSIS TYPE-2 GENE-PRODUCT (NF2 MERLIN)/

Previously, we have cloned a candidate for the 595-amino acid neurofib romatosis type 2 tumor suppressor called NF2 or Merlin, with striking sequence similarity in its N-terminal half to an F-actin-binding prote in family called TERM, which includes talin, ezrin, radixin, and moesi n (Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pula ski, It, Haase, V. H., Ambrose, C. M., Munro, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., and Gusella, J. F. (1993) Cell 72, 791-800). In an at tempt to determine whether NF2 serves as a tumor suppressor and if so whether its N terminal half is involved in its anti-oncogenicity, both fall-length NF2 and its N-terminal half (NF2-N, residues 9-359) have been expressed in v-Ha-Ras-transformed NIH/3T3 cells. Like neurofibrom atosis type 1 (NF1) fragments (Nur-E-Kamal, M. S. A., Varga, M., and M aruta, H. (1993) J. Biol. Chem. 268, 22331-22337), full-length NF2 can reverse the Ras-induced malignant phenotype, i.e. anchorage-independe nt growth in a soft agar, and restore contact inhibition of cell growt h, indicating that NF2 is indeed a tumor suppressor. Furthermore, NF2- N also suppresses the Ras-induced malignant phenotype, although it app ears to be less effective than the full-length NF2. These observations indicate that the anti-Ras function of NF2 resides in part in its N-t erminal half, Thus, NF2 appears to be a new member of the tumor suppre ssor family of actin-cytoskeleton-associated proteins, which includes vinculin, alpha-actinin, tropomyosin-1, gelsolin, and tensin.