Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin

Meng, Jin-Jun; Lowrie, D.J.; Sun, Hao; Dorsey, Emily; Pelton, Patricia D.; Bashour, Anne-Marie; Groden, Joanna; Ratner, Nancy; Ip, Wallace

doi:10.1002/1097-4547(20001115)62:4<491::aid-jnr3>3.0.co;2-d

Cited by 54 publications

(46 citation statements)

References 49 publications

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“…In this regard, merlin exists in 'open' (inactive form) and 'closed' (active growth suppressive form) conformations that are regulated by an intramolecular association between the N-and Ctermini of the protein (Gutmann et al, , 1999aGonzalez-Agosti et al, 1999;Meng et al, 2000). Merlin isoform I containing exon 17 (amino-acid residues LTLQSAKSRVAFFEEL) can form an N-term/C-term intramolecular complex ('closed' conformation).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to binding to HRS, merlin associates with the CD44 cell surface glycoprotein, schwannomininteracting protein-1 (SCHIP1), bII-spectrin or fodrin, and other ERM proteins (Sainio et al, 1997;Scoles et al, 1998;Goutebroze et al, 2000;Meng et al, 2000;Morrison et al, 2001). The importance of the interaction with CD44 is underscored by the observation that interference with merlin binding to CD44 impairs merlin growth suppression in RT4 rat schwannoma cells (Morrison et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

et al. 2004

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The neurofibromatosis 2 (NF2) tumor suppressor protein, merlin, functions as a negative growth regulator; however, the molecular mechanisms that underlie merlin regulation remain elusive. Recent studies have implicated merlin phosphorylation in regulating merlin subcellular localization and growth suppression. P21-activated kinase (PAK), a downstream target of Rac1/Cdc42, directly phosphorylates merlin at Serine 518. In this report, we show that PAK2 directly phosphorylates wild-type merlin, whereas merlin truncation mutants with impaired GST-aminoterminal domain (N-term or NTD)/GST-carboxy-terminal domain (C-term or CTD) intramolecular association exhibit impaired S518 phosphorylation. We directly demonstrate that PAK2 phosphorylation impairs merlin N-term/C-term binding in vitro and in vivo. Lastly, we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins, CD44 and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), both critical for merlin growth suppression. These observations suggest that merlin S518 phosphorylation directly modulates merlin intramolecular and intermolecular associations important for the ability of merlin to function as a tumor suppressor.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

et al. 2004

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“…This interaction may have interesting functional implications in light of published evidence that merlin isoforms 1 and 2 can interact with one another [19,23] and that this interaction can compete effectively with the interaction of isoform 1 with ezrin [23]. The idea that merlin isoforms can bind one another or ERM proteins and thereby modulate their activity is also inherent in a study of the hierarchical strengths of interaction among the N-and C-termini of merlin, ezrin and their binding partners [29].…”

Section: Discussionmentioning

confidence: 99%

“…Previous data have suggested that these isoforms are expressed at roughly equivalent levels, with isoform 2 being slightly more prevalent [6]. These two forms can be distinguished from one another by RT-PCR amplification of the NF2 transcript near the 3′ end of the open reading frame [23]. Using primers designed to amplify the NF2 transcript from exon 13 to the 5′ end of exon 17 ( Fig.…”

Section: Confirmation Of the Nf2 Mutation In Hei-193 Cellsmentioning

confidence: 99%

“…We and others have shown previously that merlin isoforms 1 and 2 can directly bind to one another [19,23] and that interactions amongst merlin isoforms can modulate merlin:ezrin interactions in vivo [23]. Thus, it would be of interest to know whether merlin isoform 3 could directly interact with isoforms 1 and 2.…”

Section: Merlin Isoform 3 Can Interact With Isoforms 1 Andmentioning

confidence: 99%

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Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Lepont

Stickney

Foster

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by the formation of bilateral schwannomas of the eighth cranial nerve. Although the protein product of the NF2 gene (merlin) is a classical tumor suppressor, the mechanism by which merlin suppresses cell proliferation is not fully understood. The availability of isolated tumor cells would facilitate a better understanding of the molecular function of merlin, but primary schwannoma cells obtained from patients grow slowly and do not yield adequate numbers for biochemical analysis. In this study, we have examined the NF2 mutation in HEI-193 cells, an immortalized cell line derived from the schwannoma of an NF2 patient. Previous work showed that the NF2 mutation in HEI-193 cells causes a splicing defect in the NF2 transcript. We have confirmed this result and further identified the resultant protein product as an isoform of merlin previously designated as isoform 3. The level of isoform 3 protein in HEI-193 cells is comparable to the levels of merlin isoforms 1 and 2 in normal human Schwann cells and several other immortalized cell lines. In contrast to many mutant forms of merlin, isoform 3 is as resistant to proteasomal degradation as isoforms 1 and 2 and can interact with each of these isoforms in vivo. Cell proliferation assays showed that, in NF2 −/− mouse embryonic fibroblasts, exogenously expressed merlin isoform 3 does exhibit growth suppressive activity although it is significantly lower than that of identically expressed merlin isoform 1. These results indicate that, although HEI-193 cells have undetectable levels of merlin isoforms 1 and 2, they are, in fact, not a merlin-null model because they express the moderately active growth-suppressive merlin isoform 3.

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Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

2021

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Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non‐mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non‐NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non‐NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

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Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin

Cited by 54 publications

References 49 publications

Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity

Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

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