Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing

Cole, Banumathi K.; Curto, Monica; Chan, Annie W.; McClatchey, Andrea I.

doi:10.1128/mcb.01139-07

Cited by 88 publications

(112 citation statements)

References 49 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…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)(9)(10). Merlin also exhibits a punctate distribution that has been attributed to localization to intracellular vesicles (7,11,12).…”

mentioning

confidence: 62%

“…Both in vivo and in cultured cells, Merlin together with Expanded, have been shown to regulate cell growth and differentiation by promoting phosphorylation and cytoplasmic retention of the transcriptional coactivator Yorkie/YAP1 (12,(21)(22)(23). Moreover, recent studies suggest that through localization at the cortical actin network, Merlin controls the internalization and signaling of certain membrane receptors, including the epidermal growth factor (6,9,(24)(25)(26)(27). These results highlight the importance of proper Merlin targeting to this region.…”

mentioning

confidence: 77%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 62%

mentioning

confidence: 77%

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.

View full text Add to dashboard Cite

show abstract

“…On this basis, it has been argued that Merlin mediates both contact inhibition and tumour suppression by directly modulating mitogenic signal transduction at or near the plasma membrane [21,22]. Analysis of various cell types indicated that Merlin can potentially affect a variety of mitogenic pathways, such as Rac-PAK signalling [7,[23][24][25], activation of mTORC1 independently of Akt [26,27], the EGFR-Ras-ERK path- [26,27], the EGFR-Ras-ERK path-,27], the EGFR-Ras-ERK pathway, the PI3K-Akt pathway and FAK-Src signalling [28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

“…Published work from the McClatchey lab suggests that merlin can coordinate the process of adherens junction stabilization with silencing of the epidermal growth factor receptor (EGFR), thereby mediating contact-dependent inhibition of proliferation (31,32). The McClatchey group has shown that loss of Nf2 yields several different types of tumors in mice and that pharmacological inhibitors of the epidermal growth factor receptor (EGFR) halt the over-proliferation of Nf2 -/-cells in vitro and in vivo.…”

Section: Technical Objective (Aim) 2: Consequences Of Nf1 and Nf2 Inamentioning

confidence: 99%

Preclinical Mouse Models of Neurofibromatosis

Shannon¹

2009

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTThis report describes the past four years of research performed by a Consortium of investigators who were continuously funded by this Program since 1999 to develop, characterize, and utilize strains of mice that accurately model tumors found in persons with NF1 and NF2. This Consortium has generated many novel models of NF1 and NF2-associated tumors and has exploited these strains to investigate biologic and preclinical questions. The investigators have collaborated closely and have extensively shared expertise and reagents with each other and with NF researchers around the world. These mouse strains developed through this effort are a cornerstone of NF research and are instrumental to an effort by the Children's Tumor Foundation to organize and support a preclinical network for testing therapeutics that might benefit persons with NF1 and NF2 disease. SUBJECT TERMS INTRODUCTIONBenign and malignant tumors are a major cause of morbidity and mortality in individuals with NF1 and NF2. The NF1 and NF2 genes function as tumor suppressors in humans and mice. Although a great deal has been learned about the genetics, biochemistry, and cell biology of NF1 and NF2-associated tumors, it has proven difficult to translate these advances into new treatments. Accurate, well-characterized mouse models of NF-associated tumors are invaluable resources for achieving the long-term goal of bringing improved treatments to NF patients. The overall purpose of this consortium, which is now ending after 10 years, has been to develop such models that would serve as permanent resources for the scientific community. These efforts were timely for a number of reasons.First, advances in gene targeting technologies in the late 1990s made it feasible to introduce many types of alterations into the mouse germline. Indeed, investigators who pioneered this general strategy were awarded the Nobel Prize in Medicine in 2007. The members of this research consortium developed the initial strains of Nf1 and Nf2 mutant mice, which provided major insights into a number of the complications seen in human NF1 and NF2 patients. Through this consortium effort, we engineered conditional mutant alleles of both Nf1 and Nf2 and in used these novel strains to create tractable new models for biologic and preclinical studies. Second, investigating cells from these Nf1 and Nf2 mutant mice has provided numerous fundamental insights that are directly relevant to understanding deregulated growth in NF1 and NF2-deficient human cells. Genetic analys...

show abstract

Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing

Cited by 88 publications

References 49 publications

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

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

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

Preclinical Mouse Models of Neurofibromatosis

Contact Info

Product

Resources

About