Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

Johnson, Kristen C.; Kissil, Joseph L.; Fry, Jessica; Jacks, Tyler

doi:10.1038/sj.onc.1205693

Cited by 47 publications

(52 citation statements)

References 31 publications

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“…Nevertheless, it facilitates phosphorylation of serine 518 and therefore participates in the regulation of the growth-inhibition activity of merlin-1. Identification of merlin functional domains Interestingly, two well-characterized dominant-negative forms of merlin both harbor deletions in the F2 subdomain, the 'blue-box' and the 'delta exons 2-3 mutants', which are both capable of overcoming endogenous merlin activity in vivo (Giovannini et al, 1999;Johnson et al, 2002;LaJeunesse et al, 1998). These findings support our conclusions that the F2 subdomain plays a crucial role in growth inhibition.…”

Section: Discussionsupporting

confidence: 77%

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells

Lallemand

Saint-Amaux

Giovannini

2009

Journal of Cell Science

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Section: Discussionsupporting

confidence: 77%

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells

Lallemand

Saint-Amaux

Giovannini

2009

Journal of Cell Science

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“…To investigate whether specific miRNAs participate in this response, we profiled miRNA expression in subconfluent and confluent cultures of primary human fibroblasts and immortalized murine fibroblasts (NIH 3T3 cells), cell lines that undergo a wellcharacterized proliferation arrest upon cell-cell contact (23). As a control, we also examined miRNA expression under identical conditions in HeLa cells, a cancer cell line that does not exhibit contact inhibition (24).…”

Section: Resultsmentioning

confidence: 99%

Cell–cell contact globally activates microRNA biogenesis

Hwang¹,

Wentzel²,

Mendell

2009

Proc. Natl. Acad. Sci. U.S.A.

127

110

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MicroRNAs (miRNAs) are 18-to 24-nt RNA molecules that regulate messenger RNAs (mRNAs). Posttranscriptional mechanisms regulate miRNA abundance during development as well as in cancer cells where miRNAs frequently exhibit dysregulated expression. The molecular mechanisms that govern the global efficiency of miRNA biogenesis in these settings remain incompletely understood, and experimental systems for the biochemical dissection of these pathways are currently lacking. Here, we demonstrate that miRNAs are subject to dynamic posttranscriptional regulation in widely used cell culture systems. As diverse mammalian and Drosophila cell lines are grown to increasing density, miRNA biogenesis is globally activated, leading to elevated mature miRNA levels and stronger repression of target constructs. This broad increase in miRNA abundance is associated with enhanced processing of miRNAs by Drosha and more efficient formation of RNA-induced silencing complexes. These findings uncover a critical parameter necessary for accurate analysis of miRNAs in cell culture settings, establish a tractable system for the study of regulated miRNA biogenesis, and may provide insight into mechanisms that influence miRNA expression in physiologic and pathophysiologic states.Drosha ͉ RNA-induced silencing complex

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“…Many NF2 mutations of Merlin are abnormally distributed in the cells and lack tumor-suppressor activity (14, 15). Moreover, when overexpressed, these mutant versions of Merlin exhibit oncogenic properties, act in a dominantnegative manner, and interfere with the activity of the WT protein (13,16,17). How the NF2 mutant protein alters the functional properties of WT Merlin remains unclear, however.…”

mentioning

confidence: 99%

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

Benseñor

Barlan²,

Rice

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The neurofibromatosis type 2 (NF2) tumor-suppressor protein Merlin is a member of the ERM family of proteins that links the cytoskeleton to the plasma membrane. In humans, mutations in the NF2 gene cause neurofibromatosis type-2 (NF2), a cancer syndrome characterized by the development of tumors of the nervous system. Previous reports have suggested that the subcellular distribution of Merlin is critical to its function, and that several NF2 mutants that lack tumor-suppressor activity present improper localization. Here we used a Drosophila cell culture model to study the distribution and mechanism of intracellular transport of Merlin and its mutants. We found that Drosophila Merlin formed cytoplasmic particles that move bidirectionally along microtubules. A single NF2-causing amino acid substitution in the FERM domain dramatically inhibited Merlin particle movement. Surprisingly, the presence of this immotile Merlin mutant also inhibited trafficking of the WT protein. Analysis of the movement of WT protein using RNAi and pull-downs showed that Merlin particles are associated with and moved by microtubule motors (kinesin-1 and cytoplasmic dynein), and that binding of motors and movement is regulated by Merlin phosphorylation. Inhibition of Merlin transport by expression of the dominant-negative mutant or depletion of kinesin-1 results in increased nuclear accumulation of the transcriptional coactivator Yorkie. These results demonstrate the requirement of microtubule-dependent transport for Merlin function.M erlin is a tumor-suppressor protein of the ERM family encoded by the NF2 gene that controls cell growth and contact-dependent inhibition of proliferation. Mutations in the NF2 gene are the underlying cause of neurofibromatosis type 2 (NF2), a familial cancer syndrome characterized by the development of sporadic tumors of the nervous system (1-3). To gain insight into Merlin's cellular functions, we have studied a Drosophila Merlin homolog and its disease-causing mutant. Drosophila Merlin shares the same fundamental domain composition as its mammalian counterpart, and several groups have obtained comparable results using the mammalian and Drosophila proteins (4).Merlin functions by organizing membrane domains that connect signals coming from the extracellular environment to cytoplasmic factors to ultimately regulate cellular proliferation (5-7). Consistent with this role, Merlin is concentrated in actin-rich structures, such as membrane ruffles in isolated cells and at cell-cell contacts in dense cultures (8-10). Merlin also exhibits a punctate distribution that has been attributed to localization to intracellular vesicles (7,11,12). Merlin has a dynamic distribution in Drosophila S2 cells. Studies have shown that the protein is initially localized along the cell cortical region and is then internalized in the form of particles (12, 13).Merlin mislocalization is associated with abnormal tissue growth and proliferation (12, 13). Many NF2 mutations of Merlin are abnormally distributed in the cells and lack tumor...

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Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

Cited by 47 publications

References 31 publications

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells

Cell–cell contact globally activates microRNA biogenesis

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

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