Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2

Rouleau, Guy A.; Merel, P.; Lutchman, Mohini; Sanson, Marc; Zucman, Jessica; Marineau, Claude; Hoang-Xuân, Khê; Demczuk, Suzanne; Desmaze, Chantal; Plougastel, Béatrice; Pulst, Stefan M.; Lenoir, Gilbert; Bijlsma, Emilia K.; Fashold, Raimund; Dumanski, Jan P.; Jong, Pieter J. de; Parry, Dilys M.; Eldrige, Roswell; Aurias, Alain; Delattre, Olivier; Thomas, Gilles

doi:10.1038/363515a0

Cited by 1,252 publications

(752 citation statements)

References 35 publications

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“…It is caused by inactivation of the NF2 gene located on chromosome 22q [2,3]. NF2 patients develop multiple central nervous system (CNS) and peripheral nervous system (PNS) tumours.…”

Section: Sidebar B | Clinical Features Of Nf2mentioning

confidence: 99%

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4 DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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“…It is caused by inactivation of the NF2 gene located on chromosome 22q [2,3]. NF2 patients develop multiple central nervous system (CNS) and peripheral nervous system (PNS) tumours.…”

Section: Sidebar B | Clinical Features Of Nf2mentioning

confidence: 99%

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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“…CD44 and ezrin play important roles in promoting tumor metastasis (Yu et al, 1997;Stamenkovic 1999, 2000;Yu et al, 2004;Khanna et al, 2001Khanna et al, , 2004, whereas merlin acts as a tumor suppressor (Rouleau et al, 1993;Trofatter et al, 1993;Lutchman and Rouleau, 1995;Sherman et al, 1997;McClatchey et al, 1998;Giovannini et al, 1999Giovannini et al, , 2000. Thus far, the functional relationship between CD44 and merlin and the manner in which CD44 affects the tumor-suppressing activity of merlin have not been established.…”

Section: Increased Expression Of Merlin Inhibits the Binding Of Fluormentioning

confidence: 99%

“…The product of the NF2 gene is schwannomin/merlin, which shares significant sequence homology with the ezrin-radixin-moesin (ERM) proteins (Rouleau et al, 1993;Trofatter et al, 1993). Merlin and the ERM proteins are members of the band 4.1 superfamily, all of which contain a FERM (4.1, ezrin, radixin, moesin) domain at their NH 2 -termini.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

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“…The NF2 gene encodes a 595 amino-acid protein Merlin (schwannomin), which is related to the Ezrin-Radixin-Moesin (ERM) protein family and was hence dubbed Merlin for Moesin, Ezrin, Radixin-like protein (Rouleau et al, 1993;Trofatter et al, 1993). Merlin is putative tumor suppressor that is anchored at cell membrane where it links transmembrane receptors to the actin cytoskeleton (Xu and Gutmann, 1998;den Bakker et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

Huang

Chen

2008

Oncogene

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Inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene function has been observed not only in familial schwannomas and other central nervous system tumors, but also in malignant tumors unrelated to the NF2 syndrome, indicating a broader role of NF2 in human tumorigenesis. The NF2-encoded protein Merlin is closely related to the Ezrin-Radixin-Moesin family of membrane/ cytoskeleton linker proteins, and has been demonstrated to suppress tumor growth by inhibiting extracellular signal-regulated kinase (ERK) and Rac1 activation. Interestingly, serum deprivation has been shown to regulate Merlin at the protein level, however, exactly how such condition affects Merlin remains elusive. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasomemediated degradation. Consistently, VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation. Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin.

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Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2

Cited by 1,252 publications

References 35 publications

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

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