Disease relevance of Nf2

• Recent studies suggest that Nf2 loss also contributes to tumor metastasis [1].
• Biallelic mutations in the neurofibromatosis 2 (NF2) gene are linked to schwannoma and meningioma tumorigenesis [2].
• Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2 [3].
• However, Nf2 hemizygous mice do not develop schwannomas but mainly osteosarcomas [3].
• Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates [4].

High impact information on Nf2

• Merlin colocalizes and interacts with adherens junction (AJ) components in confluent wild-type cells, suggesting that the lack of AJs and contact-dependent growth arrest in Nf2(-/-) cells directly results from the absence of merlin at sites of cell:cell contact [1].
• Mutation of the Neurofibromatosis 2 (NF2) tumor suppressor gene leads to cancer development in humans and mice [1].
• We show that, beginning at four months of age, thirty percent of mice with arachnoidal cell Cre-mediated excision of Nf2 exon 2 developed a range of meningioma subtypes histologically similar to the human tumors [5].
• The neurofibromatosis-2 (NF2) gene encodes merlin, an ezrin-radixin-moesin-(ERM)-related protein that functions as a tumor suppressor [6].
• At high cell density, merlin becomes hypo-phosphorylated and inhibits cell growth in response to hyaluronate (HA), a mucopolysaccharide that surrounds cells [6].

Chemical compound and disease context of Nf2

• Merlin is a tumor suppressor whose inactivation underlies the familial schwannomas and meningiomas of neurofibromatosis 2 and their sporadic counterparts [7].

Biological context of Nf2

• Merlin is regulated by phosphorylation in a Rac/cdc42-dependent fashion [8].
• Using an antibody that recognizes the carboxy-terminal epitope of isoform 1 of schwannomin, we looked at its expression in lens and Schwann cells, two cell-types affected by the NF2 phenotype [9].
• Its level of expression in the lens inversely correlates with the degree of lens cell differentiation suggesting a role for schwannomin in differentiation-specific events [9].
• In order to analyze the function of merlin during embryogenesis and to develop a system to study merlin function in detail, we have disrupted the mouse Nf2 gene by homologous recombination in embryonic stem cells [10].
• Merlin/Schwannomin is a tumor suppressor protein that has been reported to block the Ras-mediated cell proliferation and -anchorage-independent cell growth [11].

Anatomical context of Nf2

• In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant Sch Delta 81-121, but not wild type Sch, was also degraded by proteasomes [12].
• Erbin regulates mitogen-activated protein (MAP) kinase activation and MAP kinase-dependent interactions between Merlin and adherens junction protein complexes in Schwann cells [2].
• The NF2 gene product, merlin, associates with adherens junction protein complexes, suggesting that part of its function as a tumor suppressor involves regulating cell junctions [2].
• Our results show that schwannomin and integrin beta1 can be associated with paranodin in the central nervous system [13].
• We show that the FERM domain of schwannomin binds to the paranodin GNP motif in glutathione S-transferase (GST)-pull down assays and in transfected COS-7 cells [13].

Associations of Nf2 with chemical compounds

• We report that the phosphorylation of merlin at serine 518 is induced by the p21-activated kinase PAK2 [8].
• The presence of paranodin increased the association between integrin beta1 and schwannomin or its N-terminal domain, suggesting that the interactions between these proteins are interdependent [13].
• To determine whether schwannomin may affect cell growth, we transfected NIH 3T3 cells with the wild type and an NF2 cDNA lacking 111 amino acids at the NH2 terminus [14].
• Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain [15].
• In this report, merlin was demonstrated to be effective in suppressing the NF-kappaB signaling pathway in NIH3T3 and C6 cells [16].

Physical interactions of Nf2

• Moreover, it was shown that merlin interacted with endogenous growth factor receptor bound 2 (Grb2) protein and inhibited its expression [17].

Enzymatic interactions of Nf2

• Cells with NF2 mutations exhibit elevated levels of phosphorylated extracellular signal-regulated kinase (ERK) and aberrant cell-cell and cell-matrix contacts [2].

Regulatory relationships of Nf2

• Presently, how NF2 is expressed during embryonic development and in the tissues affected by neurofibromatosis type 2 (NF2) has not been well defined [18].
• These results suggest that merlin inhibits SRE dependent transactivation by repressing serum-induced ERK phosphorylation and its downstream effector, Elk phosphorylation [19].

Other interactions of Nf2

• Here, we find that a novel PDZ protein, called erbin, binds directly to the merlin-binding partner, EBP0, and regulates adherens junction dissociation through a MAP kinase-dependent mechanism [2].
• Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization [8].
• 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 [12].
• In transfected cells, Sch Delta F118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation [12].
• By using wild-type and mutated forms of merlin and phospho-directed antibodies, we show that phosphorylation of merlin at serine 518 leads to dramatic protein relocalization [8].

Analytical, diagnostic and therapeutic context of Nf2

• Indirect immunofluorescence localized schwannomin to the cytoplasm and was frequently observed in dynamic cellular regions such as leading edges and ruffling membranes [9].
• In situ hybridization showed that Nf2 is expressed in neuronal cells as well as in epithelial and fibre cells of the lens [20].
• Molecular cloning and characterization of alternatively spliced transcripts of the mouse neurofibromatosis 2 gene [21].
• Gene therapy for schwannomas was evaluated in two mouse models of neurofibromatosis type 2 (NF2): (1) a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas, and (2) a xenograft model in which human schwannoma tissue is implanted subcutaneously into immune- compromised mice [22].

References