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Papers In Press, published online ahead of print July 18, 2002
UMR144- CNRS/Institut Curie, Curie Institute, Paris cedex 05 75248
Corresponding Author: marpin{at}curie.fr
Neurofibromatosis type 2 (NF2), a syndrome associated with multiple tumors of the nervous system, mostly schwannomas, is caused by mutations in the NF2 tumor suppressor gene that encodes schwannomin (Sch). Here we examined NF2 pathogenetic mutations that result in misfolding of the FERM domain. We found that these mutant forms of Sch were efficiently degraded by the ubiquitin-proteasome pathway. In transfected cells, SchDF118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation. In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant SchD81-121, but not wild type Sch, was also degraded by proteasomes. We further show that this degradation pathway is functional in primary Schwann cells. We analyzed SchD39-121 expressed in a transgenic mouse model of NF2, and found that SchD39-121, but not the endogenous wild type Sch, was unstable due to proteasome mediated degradation. Altogether, these results suggest that degradation of mutant Sch mediated by the ubiquitin-proteasome pathway is a physiopathological pathway contributing to the loss of Sch function in NF2 patients.
J. Biol. Chem, 10.1074/jbc.C200125200
Submitted on March 4, 2002
Revised on July 17, 2002
Accepted on July 18, 2002
Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin-proteasome pathway
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