Ezrin–radixin–moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia

Morales, Fabiana C.; Takahashi, Yoko; Kreimann, Erica L.; Georgescu, Maria Magdalena

doi:10.1073/pnas.0407974101

Cited by 201 publications

(242 citation statements)

References 24 publications

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“…To the same extent, the mutant PDZ1-2, which lacks the ERMbinding (EB) region, suppressed colony formation, whereas all the other mutants had no effect or slightly increased growth in soft agar. Notably, the naturally occurring splice isoform I2 that lacks the PDZ2 domain (Morales et al, 2004) was unable to suppress growth, indicating that both PDZ domains are required for anchorage-independent growth suppression by NHERF1.…”

Section: Resultsmentioning

confidence: 99%

“…In vivo, we have described previously structural defects of the brush-border membrane (BBM) of intestinal epithelial cells in NHERF1(À/À) mice (Morales et al, 2004). Fractionation of intestinal BBM , cytoplasmic (C), membrane (M), cytoskeleton (Cs) and debris (D) fractions.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, Shibata et al (2003) reported that the NHERF1/b-catenin complex promotes Wnt signaling and may cooperate in the development of liver cancer. To clarify the role of NHERF1, we analysed the growth properties of mouse embryonic fibroblasts (MEFs) generated from NHERF1-deficient mice (Morales et al, 2004). We found that NHERF1(À/À) immortalized MEFs, in contrast to their wild-type counterparts, presented anchorage-independent growth.…”

Section: Introductionmentioning

confidence: 99%

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Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

et al. 2007

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Anchorage-independent growth is a hallmark of tumor growth and results from enhanced proliferation and altered cell-cell and cell-matrix interactions. By using genedeficient mouse embryonic fibroblasts (MEFs), we showed for the first time that NHERF1/EBP50 (Na/H exchanger regulator factor 1/ezrin-radixin-moesin binding phosphoprotein 50), an adapter protein with membrane localization under physiological conditions, inhibits cell motility and is required to suppress anchorage-independent growth. Both NHERF1 PDZ domains are necessary for the tumor suppressor effect. NHERF1 associates directly through the PDZ2 domain with b-catenin and is required for b-catenin localization at the cell-cell junctions in MEFs. Mechanistically, the absence of NHERF1 selectively decreased the interaction of b-catenin with E-cadherin, but not with N-cadherin. The ensuing disorganization of E-cadherinmediated adherens junctions as well as the observed moderate increase in b-catenin transcriptional activity contributed most likely to the anchorage-independent growth of NHERF1-deficient MEFs. In vivo, NHERF1 is specifically localized at the apical brush-border membrane in intestinal epithelial cells and is required to maintain a fraction of the cortical b-catenin at this level. Thus, NHERF1 emerges as a cofactor essential for the integrity of epithelial tissues by maintaining the proper localization and complex assembly of b-catenin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

et al. 2007

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“…EBP50 is required for the maintenance of active ERM proteins at the cortical brush border membranes of polarized epithelia. 2 In addition, EBP50 assembles multiprotein complexes that anchor transporters to the apical actin cytoskeleton and facilitate their regulation. The liver is the tissue that displays the highest level of EBP50 expression.…”

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confidence: 99%

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Fouassier

Rosenberg

Mergey

et al. 2009

The American Journal of Pathology

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Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) anchors and regulates apical membrane proteins in epithelia. EBP50 is inducible by estrogen and may affect cell proliferation, although this latter function remains unclear. The goal of this study was to determine whether EBP50 was implicated in the ductular reaction that occurs in liver disease. EBP50 expression was examined in normal human liver, in human cholangiopathies (ie, cystic fibrosis, primary biliary cirrhosis, and primary sclerosing cholangitis), and in rats subjected to bile-duct ligation. The regulation of EBP50 by estrogens and its impact on proliferation were assessed in both bile duct-ligated rats and Mz-Cha-1 human biliary epithelial cells. Analyses of cell isolates and immunohistochemical studies showed that in normal human liver, EBP50 is expressed in the canalicular membranes of hepatocytes and, together with ezrin and cystic fibrosis transmembrane conductance regulator, in the apical domains of cholangiocytes. In both human cholangiopathies and bile duct-ligated rats, EBP50 was redistributed to the cytoplasmic and nuclear compartments. EBP50 underwent a transient increase in rat cholangiocytes after bile-duct ligation, whereas such expression was down-regulated in ovariectomized rats. In addition, in Mz-Cha-1 cells, EBP50 underwent upregulation and intracellular redistribution in response to 17␤-estradiol, whereas its proliferation was inhibited by siRNA-mediated EBP50 knockdown. These results indicate that both the expression and distribution of EBP50 are regulated by estrogens and contribute to the proliferative response in biliary epithelial cells. (Am J

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“…Therefore, the expression of ezrin correlates with NHERF-1 and NHERF-2 in the stereocilia during early postnatal development. Strong evidence has also been provided that NHERF-1 and NHERF-2 can organize ERM proteins in specific functional clusters at the plasma membrane (Morales et al 2004). Therefore, NHERFs probably play a significant role in organizing actin and associated proteins in the developing stereocilia.…”

Section: Discussionmentioning

confidence: 99%

Postnatal developmental expression of the PDZ scaffolds Na+-H+ exchanger regulatory factors 1 and 2 in the rat cochlea

et al. 2005

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Sensory transduction in the mammalian cochlea requires the maintenance of specialized fluid compartments with distinct ionic compositions. This is achieved by the concerted action of diverse ion channels and transporters, some of which can interact with the PDZ scaffolds, Na + -H + exchanger regulatory factors 1 and 2 (NHERF-1, NHERF-2). Here, we report that NHERF-1 and NHERF-2 are widely expressed in the rat cochlea, and that their expression is developmentally regulated. Reverse transcription/polymerase chain reaction (RT-PCR) and Western blotting initially confirmed the RNA and protein expression of NHERFs. We then performed immunohistochemistry on cochlea during various stages of postnatal development. Prior to the onset of hearing (P8), NHERF-1 immunolabeling was prominently polarized to the apical membrane of cells lining the endolymphatic compartment, including the stereocilia and cuticular plates of the inner and outer hair cells, marginal cells of the stria vascularis, Reissner's epithelia, and tectorial membrane. With maturation (P21, P70), NHERF-1 immunolabeling was reduced in the above structures, whereas labeling increased in the apical membrane of the interdental cells of the spiral limbus and the inner and outer sulcus cells, Hensen's cells, the inner and outer pillar cells, Deiters cells, the inner border cells, spiral ligament fibrocytes, and spiral ganglion neurons (particularly type II). NHERF-1 expression in strial basal and intermediate cells was persistent. NHERF-2 immunolabeling was similar to that for NHERF-1 during postnatal development, with the exception of expression in the synaptic regions beneath the outer hair cells. NHERF-1 and NHERF-2 co-localized with glial fibrillary acidic protein and vimentin in glia. The cochlear localization of NHERF scaffolds suggests that they play important roles in the developmental regulation of ion transport, homeostasis, and auditory neurotransmission.

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Ezrin–radixin–moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia

Cited by 201 publications

References 24 publications

Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Postnatal developmental expression of the PDZ scaffolds Na+-H+ exchanger regulatory factors 1 and 2 in the rat cochlea

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