Contact-dependent inhibition of EGFR signaling by Nf2/Merlin

Curto, Monica; Cole, Banumathi K.; Lallemand, Dominique; Liu, Ching-Hui; McClatchey, Andrea I.

doi:10.1083/jcb.200703010

Cited by 327 publications

(366 citation statements)

References 64 publications

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“…Merlin has been proposed to suppress proliferation by reducing the amount of transmembrane growth factor receptors at the plasma membrane [22,74,75]. Genetic analysis in Drosophila showed that Merlin, cooperating with the FERM domain protein Expanded, promotes endocytosis of several transmembrane receptors, including some involved in mitogenic signalling [75].…”

Section: Inhibition Of Receptor Tyrosine Kinase Activationmentioning

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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Section: Inhibition Of Receptor Tyrosine Kinase Activationmentioning

confidence: 99%

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

et al. 2012

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“…EBP50 silencing elicits EMT-associated features through EGFR activation EBP50 acts as a linker between F-actin-binding molecules and cell junctional proteins (for example, b-catenin), and thereby presumably participates in cell adhesion (Curto et al, 2007;Kreimann et al, 2007). We tested whether this mechanism involves EGFR.…”

Section: Ebp50 Silencing Increases Egfr Expression and Downstream Sigmentioning

confidence: 99%

“…Therefore, our findings suggest that EBP50 may contribute to the E-cadherin/b-catenindependent intercellular adhesion by acting directly on EGFR signaling output. Curto et al (2007) demonstrated that merlin/Nf2 tethers EBP50 to the cell cytoskeleton (Murthy et al, 1998) and thereby participates in the stabilization of AJs through the regulation of EGFR. The observation that EBP50, but not merlin/ Nf2, interacts directly with EGFR (Lazar et al, 2004;Takahashi et al, 2006;Curto et al, 2007), suggests that EBP50 regulates EGFR signaling per se.…”

Section: Loss Of Ebp50-egfr Interplay In Biliary Carcinomamentioning

confidence: 99%

“…In cells expressing EBP50 beneath the plasma membrane (left panel), EBP50 interacts with EGFR and with b-catenin through its PDZ1 and PDZ2 domains, respectively (Shibata et al, 2003;Lazar et al, 2004;Takahashi et al, 2006) at AJs (Kreimann et al, 2007). The association of EBP50 with cell cytoskeleton via the ERM proteins contributes to cortical stabilization of the b-catenin/E-cadherin complex (Curto et al, 2007;Kreimann et al, 2007). In the absence of EBP50 at the plasma membrane, loss of EBP50-EGFR interaction (right panel) causes an increase of EGFR expression at the cell surface and a sustained activation of the receptor and of its downstream effectors (ERK and STAT3).…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

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Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

et al. 2011

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Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.

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“…Moreover, Nf2 inactivation results in destabilization of adherens junctions (AJs) that are essential for contact inhibition of proliferation in mouse embryonic fibroblasts (MEFs) (Lallemand et al, 2003). In addition, merlin can block ligandinduced epidermal growth factor receptor internalization and signaling in various cell types (Curto et al, 2007). In a rat schwannoma cells, merlin also inhibits growth by promoting platelet-derived growth factor receptor (PDGFR) degradation (Fraenzer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

et al. 2008

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The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cellto-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and plateletderived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

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Contact-dependent inhibition of EGFR signaling by Nf2/Merlin

Cited by 327 publications

References 64 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

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

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