1. ¹Catholic Neuroscience Center, The Catholic University of Korea, Seoul 137-701, Korea
2. ²Department of Urology, The Catholic University of Korea, Seoul 137-701, Korea
3. ³Department of Pharmacology, The Catholic University of Korea, Seoul 137-701, Korea
4. ⁴Department of Occupational and Environmental Medicine, The Catholic University of Korea, Seoul 137-701, Korea
5. ⁵Department of Psychiatry, The Catholic University of Korea, Seoul 137-701, Korea

Correspondence: T-Y Jun, Department of Psychiatry, The Catholic University of Korea, 505 Banpo dong, Socho ku, Seoul 137-701, Korea. E-mail: ngrc@catholic.ac.kr

Received 17 November 2004; Revised 7 February 2005; Accepted 14 February 2005; Published online 27 June 2005.

Abstract

Neurofibromatosis type 2 (NF2) is the most commonly mutated gene in benign tumors of the human nervous system such as schwannomas and meningiomas. The NF2 gene encodes a protein called schwannomin or merlin, which is involved in regulating cell growth and proliferation through protein–protein interactions with various cellular proteins. In order to better understand the mechanism by which merlin exerts its function, yeast two-hybrid screening was performed and Ral guanine nucleotide dissociation stimulator (RalGDS), a downstream molecule of Ras, was identified as a merlin-binding protein. The direct interaction between merlin and RalGDS was confirmed both in vitro and in the NIH3T3 cells. The domain analyses revealed that the broad C-terminal region of merlin (aa 141–595) is necessary for the interaction with the C-terminal Ras-binding domain (RBD) of RalGDS. Functional studies showed that merlin inhibits the RalGDS-induced RalA activation, the colony formation and the cell migration in mammalian cells. These results suggest that merlin can function as a tumor suppressor by inhibiting the RalGDS-mediated oncogenic signals.