ERM-Merlin and EBP50 Protein Families in Plasma Membrane Organization and Function

Bretscher, Anthony; Chambers, Diana; Nguyen, Rachel; Reczek, David

doi:10.1146/annurev.cellbio.16.1.113

Cited by 349 publications

(319 citation statements)

References 172 publications

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“…Ezrin, another member of the ERM family, is reported to participate in Src signaling and to induce FAK activation (Poullet et al, 2001;Srivastava et al, 2005) Although ezrin and merlin have similarities in structure and common interacting partners, such as CD44, NHERF and N-WASP (Bretscher et al, 2000;Morrison et al, 2001;Martin et al, 2003;Manchanda et al, 2005), they possess opposite functions in cell growth and proliferation. As we observed an inhibitory effect of merlin on cell migration and invasion, we sought to determine if merlin could downregulate FAK.…”

Section: Re-expression Of Merlin Attenuates Fak Phosphorylation At Tymentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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Section: Re-expression Of Merlin Attenuates Fak Phosphorylation At Tymentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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“…Subsequently, activated ERM proteins are translocated from the cytosol to the membrane-cytoskeleton interface. Moreover, binding of phosphatidylinositol 4,5-biphosphate (PIP 2 ) to the NT domain is a prerequisite for ERM proteins to be phosphorylated and activated (Bretscher et al, 2000;Gervais et al, 2008). Functionally, ERM proteins have been implicated in signifying specialized membrane domains, promoting cell cytoskeleton remodeling and Rho GTPase activation, and inducing signal transduction (Bretscher et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, binding of phosphatidylinositol 4,5-biphosphate (PIP 2 ) to the NT domain is a prerequisite for ERM proteins to be phosphorylated and activated (Bretscher et al, 2000;Gervais et al, 2008). Functionally, ERM proteins have been implicated in signifying specialized membrane domains, promoting cell cytoskeleton remodeling and Rho GTPase activation, and inducing signal transduction (Bretscher et al, 2000). Several studies have also provided evidence that ERM expressions correlated with cell polarization, cell-cell or cell-ECM communication, and tumor cell transformation, motility and metastasis (Bretscher et al, 2002;McClatchey, 2003).…”

Section: Introductionmentioning

confidence: 99%

Recognition of CD146 as an ERM-binding protein offers novel mechanisms for melanoma cell migration

et al. 2011

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Tumor cell migration is a well-orchestrated multistep process that drives cancer development and metastasis. Previous data indicated that CD146 expression correlates with malignant progression and metastatic potential of human melanoma cells. However, the exact molecular mechanism of how CD146 promotes melanoma cell migration still remains poorly understood. Here, we report that CD146 physically interacts with actin-linking ezrin-radixin-moesin (ERM) proteins and recruits ERM proteins to cell protrusions, promoting the formation and elongation of microvilli. Moreover, CD146-promoted melanoma cell migration is linked to RhoA activation and ERM phosphorylation. CD146 recruits Rho guanine nucleotide dissociation inhibitory factors 1 (RhoGDI1) through ERM proteins and thus sequesters RhoGDI1 from RhoA, which leads to upregulated RhoA activity and increased melanoma cell motility. CD146-activated RhoA also promotes further ERM phosphorylation and activation through Rho-phosphatidylinositol-4-phosphate-5-kinase-phosphatidylinositol 4,5-biphosphate pathway, which reinforces CD146/ERM association. Thus, our results provide a mechanistic basis to understand the role of CD146 in regulating human melanoma cell motility.

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“…Merlin can form homo-and heterotypic interactions which in turn regulate its binding to other proteins. Unlike Merlin in an open conformation, head-to-tail binding of Merlin, which leads to a closed conformation, is thought to act as a tumor suppressor and regulates cell growth (Gonzalez-Agosti et al, 1999;Bretscher et al, 2000). Phosphorylation of a C-terminal serine (S518) by p21-activated kinase (PAK)-or cAMP-dependent protein kinase A weakens Merlin's self-association and is believed to inactivate its growth-suppressing activity.…”

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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ERM-Merlin and EBP50 Protein Families in Plasma Membrane Organization and Function

Cited by 349 publications

References 172 publications

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Recognition of CD146 as an ERM-binding protein offers novel mechanisms for melanoma cell migration

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

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