calpain and Neurofibromatosis-2

Neurofibromatosis type 2 (NF2) is a dominantly inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumours associated with the central nervous system. The NF2 protein, also known as merlin or schwannomin, is a recently cloned tumour suppressor and is mutated or inactivated in most schwannomas and meningiomas. Homology analysis indicates that merlin is most closely related to members of the protein 4.1 superfamily especially ezrin, radixin and moesin, the ERM proteins. ERM proteins link membrane proteins to the cytoskeleton. It has been speculated that disruption of a similar membrane-linking role for merlin is involved in the development of tumours. This review focuses on what is now known of the organization and role of merlin's functional domains and how its activity might be regulated. Recent evidence of post-translational regulatory mechanisms which offer hope for new drug intervention strategies to help alleviate this debilitating disease are asses sed.

Topics: Animals; Calpain; Cytoskeleton; Humans; Membrane Proteins; Neurofibromatosis 2; Neurofibromin 2; Protein Structure, Tertiary

The neurofibromatosis type 2 (NF2) protein, known as merlin or schwannomin, is a tumor suppressor, and the NF2 gene has been found to be mutated in the majority of schwannomas and meningiomas, including both sporadically occurring and familial NF2 cases. Although the development of these tumors depends on the loss of merlin, the presence of tumors lacking detectable NF2 mutations suggests different mechanisms for inactivating merlin. Recent studies have demonstrated cleavage of merlin by calpain, a calcium-dependent neutral cysteine protease, and marked activation of the calpain system resulting in the degradation of merlin in these tumors. Increased turnover of merlin by calpain in some schwannomas and meningiomas exemplifies tumorigenesis linked to the calpain-mediated proteolytic pathway.

Topics: Calpain; Genes, Neurofibromatosis 2; Humans; Membrane Proteins; Meningioma; Mutation; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Peptide Hydrolases

The neurofibromatosis Type 2 (NF2) gene is the only tumor suppressor gene that has been clearly implicated in the development of benign meningiomas. Interestingly, previous data obtained by the authors indicate that reduced NF2 protein expression seldom occurs in meningothelial meningiomas, the most common histological type of meningioma. The goal of the current study was to explore further the hypothesis of NF2 gene-independent tumorigenesis of meningothelial meningiomas.. The authors performed a mutational analysis of all 17 exons of the NF2 gene by using single-stranded conformational polymorphism (SSCP). In addition, expression levels of the NF2 protein and mu-calpain, a protease suggested to inactivate the NF2 protein, were determined by immunoblotting analysis of 27 meningiomas (20 meningothelial and seven nonmeningothelial). Mutations of the NF2 gene were found in only one (5%) of 20 meningothelial meningiomas and three (43%) of seven nonmeningothelial tumors (Fisher's exact test, p = 0.042). The levels of NF2 protein were severely reduced in six (28.5%) of 21 meningothelial meningiomas, in contrast to six (86%) of seven nonmeningothelial meningiomas (Fisher's exact test, p = 0.023). Activation of IL-calpain did not correlate with the status of NF2 protein expression in the meningiomas analyzed, demonstrating that mu-calpain activation does not account for the loss of NF2 protein in meningiomas with apparently normal NF2 genes.. These results clearly demonstrate that NF2 gene mutations and decreased NF2 protein expression rarely occur in meningothelial meningiomas compared with other histological types of meningiomas. The clinical behavior of meningothelial meningiomas, however, is similar to that of other benign meningiomas. It is likely, therefore, that the tumorigenesis of meningothelial meningiomas is the result of deleterious alterations of genes that have final phenotypical effects similar to inactivation of the NF2 gene.

Topics: Adult; Aged; Aged, 80 and over; Base Sequence; Calpain; Enzyme Activation; Female; Genes, Tumor Suppressor; Humans; Male; Membrane Proteins; Meningeal Neoplasms; Meningioma; Middle Aged; Mutation; Neurofibromatosis 2; Neurofibromin 2; Polymorphism, Single-Stranded Conformational