TY - JOUR
T1 - Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin-proteasome pathway
AU - Gautreau, Alexis
AU - Manent, Jan
AU - Fievet, Bruno
AU - Louvard, Daniel
AU - Giovannini, Marco
AU - Arpin, Monique
PY - 2002/8/30
Y1 - 2002/8/30
N2 - 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, SchδF118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation. In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant Schδ81-121, 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 Schδ39-121 expressed in a transgenic mouse model of NF2 and found that Schδ39-121, 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.
AB - 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, SchδF118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation. In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant Schδ81-121, 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 Schδ39-121 expressed in a transgenic mouse model of NF2 and found that Schδ39-121, 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.
UR - http://www.scopus.com/inward/record.url?scp=0037199912&partnerID=8YFLogxK
U2 - 10.1074/jbc.C200125200
DO - 10.1074/jbc.C200125200
M3 - Article
C2 - 12130630
AN - SCOPUS:0037199912
SN - 0021-9258
VL - 277
SP - 31279
EP - 31282
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -