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J. Biol. Chem., Vol. 278, Issue 8, 6235-6242, February 21, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/8/6235    most recent M210639200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gautreau, A. Articles by Arpin, M. Search for Related Content PubMed PubMed Citation Articles by Gautreau, A. Articles by Arpin, M. Social Bookmarking                      What's this?

Isolation and Characterization of an Aggresome Determinant in the NF2 Tumor Suppressor^*

Alexis Gautreau^§¶, Bruno T. Fievet^¶, Estelle Brault, Claude Antony, Anne Houdusse, Daniel Louvard, and Monique Arpin^**

From the  UMR144 CNRS/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France and  INSERM U434 Centre d'Etude du Polymorphisme Humain, 75010 Paris, France

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 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.

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