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J. Biol. Chem., Vol. 277, Issue 35, 31279-31282, August 30, 2002

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ACCELERATED PUBLICATION
Mutant Products of the NF2 Tumor Suppressor Gene Are Degraded by the Ubiquitin-Proteasome Pathway^*

Alexis Gautreau^§, Jan Manent^¶, Bruno Fievet, Daniel Louvard, Marco Giovannini^¶, and Monique Arpin

From the  UMR144 CNRS/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France and ^¶ INSERM U434/CEPH, 27 rue Juliette Dodu, 75010 Paris, France

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, SchF118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation. In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant Sch81-121, 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 Sch39-121 expressed in a transgenic mouse model of NF2 and found that Sch39-121, 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.

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