Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin

The product of the neurofibromatosis type II (NF2) tumor suppressor gene, merlin, is closely related to the ezrin‐radixin‐moesin (ERM) family, a group of proteins believed to link the cytoskeleton to the plasma membrane. Mutation in the NF2 locus is associated with Schwann cell tumors (schwannomas). The two predominant merlin isoforms, I and II, differ only in the carboxy‐terminal 16 residues and only isoform I is anti‐proliferative. Merlin lacks an actin‐binding domain conserved among ezrin, radixin and moesin. Because merlin, ezrin and moesin are co‐expressed in Schwann cells, and all homodimerize, we have examined whether merlin and ezrin dimerize with one another. We found by immunoprecipitation and yeast two‐hybrid assays that both merlin isoforms interact with ezrin. The interaction occurs in a head‐to‐tail orientation, with the amino‐terminal half of one protein interacting with the carboxy‐terminal half of the other. The two merlin isoforms behave differently in their interaction with ezrin. Isoform I binds only ezrin whose carboxy‐terminus is exposed, whereas isoform II binds ezrin regardless of whether ezrin is in the open or closed conformation. The heterodimerization of merlin is a much stronger interaction than the interaction between either merlin isoform and ezrin, and can inhibit merlin‐ezrin binding. This suggests that, in vivo, merlin dimerization could regulate merlin‐ERM protein interaction, and could thus indirectly regulate other interactions involving ERM proteins. J. Neurosci. Res. 62:491–502, 2000. © 2000 Wiley‐Liss, Inc.