Characterization of Neurofibromatosis 2 (NF2) Tumor

Abstract

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder that is characterized by the occurrence of vestibular schwannomas, meningiomas and other nervous system tumors. Both the familial tumors of NF2, and equivalent sporadic tumors in the general population, are caused by inactivation of a tumor suppressor gene located on chromosome band 22q12. The NF2 gene product has been named merlin (moesin, ezrin and radixin like protein) because of its striking similarity to ezrin, radixin and moesin (ERM). Regulation of the merlin and ERM proteins (MERM) involves intramolecular and intermolecular head-to-tail associations between family members. The next step is to further analyze the normal function of merlin and its role as a growth regulator. Towards this end the MERM binding protein, NHE-RF, was further characterized and other merlin binding proteins were sought.<br /> Analyses of NHE-RF expression in various tumor cell lines revealed a significant upregulation of NHE-RF expression in ER- positive breast carcinoma cell lines. In addition, 90% of the analyzed primary ER-positive breast tumors express high levels of NHE-RF. NHE-RF appears to be involved in many cellular signaling pathways, and it is likely that its regulation through estrogen plays a role in breast neoplasia. <br /> To isolate further merlin binding proteins, a yeast two-hybrid screen was conducted and revealed that a novel protein (merintA) interacts directly with merlin. The gene for human merintA lies on chromosome 4 where the predicted four exons encode a 178 amino acid protein with the Grb2 binding motif (p)YVNG. MerintA associates and co-localizes with merlin and F-actin in cultured cells and in addition, merintA binds to Grb2 directly. These findings reveal that merintA is a specific and relevant merlin binding protein and could link merlin to Grb2 signaling pathways that might reveal clues to the tumor suppressor function of merlin.