INTERDOMAIN BINDING MEDIATES TUMOR-GROWTH SUPPRESSION BY THE NF2 GENE-PRODUCT

The neurofibromatosis 2 (NF2) tumor suppressor gene encodes an intrace llular membrane-associated protein, called merlin (or schwannomin), th at belongs to the band 4.1 family of cytoskeleton-associated proteins, Inactivating NF2 mutations occur in several sporadic tumor types and have been linked to the NF2 disease, whose hallmark is the development of bilateral Schwann cell tumors (schwannomas) of the eighth cranial nerve, Two major alternatively spliced NI;2 variants are expressed in normal tissues:'NF2-17 lacking exon 16 and 'NF2-16' that contains exon 16 and encodes a merlin protein truncated at the C-terminus, We repor t that overexpression of NF2-17 in rat schwannoma cells inhibits their growth in vitro and in vivo, while NF2-16 fails to influence schwanno ma growth, Tumor growth inhibition by merlin depends on an interdomain association occurring either in cis or in hans between the N- and C-t ermini, This association does not occur in the truncated NF2-16 protei n nor in a mutant NF2-17 protein lacking C-terminal sequences, These d ata indicate that merlin has a unique mechanism of tumor suppression, inhibiting cell proliferation via self-association.