title: Isolation and characterization of an aggresome determinant in the NF2 tumor suppressor.
abstract: Schwannomin (Sch) is the product of the NF2 tumor suppressor gene. The NF2 gene is mutated in patients affected by neurofibromatosis type 2, a syndrome associated with multiple tumors of the nervous system. Here we found that Sch, when its N-terminal FERM domain was misfolded by the pathogenetic mutation Delta F118, formed aggresomes, i.e. aggregates that cluster at the centrosome as a result of microtubule-dependent transport. Strikingly the related protein ezrin affected by the same mutation did not form aggresomes even though its FERM domain was similarly misfolded. By studying ezrin/Sch chimeras, we delineated a sequence of 61 amino acids in the C terminus of Sch that determined the formation of aggresomes. Aggresome formation by these chimeras was independent from their rate of degradation. Sch(535-595) was sufficient to induce aggresomes of a green fluorescent fusion protein in vivo and aggregates of a glutathione S-transferase fusion protein in vitro. Taken together, these results suggest that aggresome formation is controlled primarily by aggresome determinants, which are distinct from degradation determinants, or from misfolding, through which aggresome determinants might be exposed.
authors.affiliation: UMR144 CNRS/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gautreau
authors.forename: Bruno T
authors.initials: BT
authors.lastname: Fievet
authors.forename: Estelle
authors.initials: E
authors.lastname: Brault
authors.forename: Claude
authors.initials: C
authors.lastname: Antony
authors.forename: Anne
authors.initials: A
authors.lastname: Houdusse
authors.forename: Daniel
authors.initials: D
authors.lastname: Louvard
authors.forename: Monique
authors.initials: M
authors.lastname: Arpin
mesh_terms: D000818:Animals; D002460:Cell Line; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D007700:Kinetics; D020125:Mutation, Missense; D016518:Neurofibromatosis 2 / Q000235:genetics*; D025581:Neurofibromin 2 / Q000235:genetics*; D015388:Organelles / Q000473:pathology / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000032:analysis; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D025581:Neurofibromin 2; D011994:Recombinant Proteins