Journal articles: 'ERM PROTEINS'

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McClatchey, Andrea I. "ERM proteins." Current Biology 22, no. 18 (September 2012): R784—R785. http://dx.doi.org/10.1016/j.cub.2012.07.057.

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McClatchey, Andrea I. "ERM proteins at a glance." Journal of Cell Science 127, no. 15 (June 20, 2014): 3199–204. http://dx.doi.org/10.1242/jcs.098343.

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Clucas, J., and F. Valderrama. "ERM proteins in cancer progression." Journal of Cell Science 127, no. 2 (January 13, 2014): 267–75. http://dx.doi.org/10.1242/jcs.133108.

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Clucas, J., and F. Valderrama. "ERM proteins in cancer progression." Journal of Cell Science 128, no. 6 (March 15, 2015): 1253. http://dx.doi.org/10.1242/jcs.170027.

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Bagchi, M., M. Katar, W. K. Lo, R. Yost, C. Hill, and H. Maisel. "ERM proteins of the lens." Journal of Cellular Biochemistry 92, no. 3 (2004): 626–30. http://dx.doi.org/10.1002/jcb.20062.

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Kondo, Takahisa, Kosei Takeuchi, Yoshinori Doi, Shigenobu Yonemura, Shigekazu Nagata, Shoichiro Tsukita, and Sachiko Tsukita. "ERM (Ezrin/Radixin/Moesin)-based Molecular Mechanism of Microvillar Breakdown at an Early Stage of Apoptosis." Journal of Cell Biology 139, no. 3 (November 3, 1997): 749–58. http://dx.doi.org/10.1083/jcb.139.3.749.

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Breakdown of microvilli is a common early event in various types of apoptosis, but its molecular mechanism and implications remain unclear. ERM (ezrin/radixin/moesin) proteins are ubiquitously expressed microvillar proteins that are activated in the cytoplasm, translocate to the plasma membrane, and function as general actin filament/plasma membrane cross-linkers to form microvilli. Immunofluorescence microscopic and biochemical analyses revealed that, at the early phase of Fas ligand (FasL)–induced apoptosis in L cells expressing Fas (LHF), ERM proteins translocate from the plasma membranes of microvilli to the cytoplasm concomitant with dephosphorylation. When the FasL-induced dephosphorylation of ERM proteins was suppressed by calyculin A, a serine/threonine protein phosphatase inhibitor, the cytoplasmic translocation of ERM proteins was blocked. The interleukin-1β–converting enzyme (ICE) protease inhibitors suppressed the dephosphorylation as well as the cytoplasmic translocation of ERM proteins. These findings indicate that during FasL-induced apoptosis, the ICE protease cascade was first activated, and then ERM proteins were dephosphorylated followed by their cytoplasmic translocation, i.e., microvillar breakdown. Next, to examine the subsequent events in microvillar breakdown, we prepared DiO-labeled single-layered plasma membranes with the cytoplasmic surface freely exposed from FasL-treated or nontreated LHF cells. On single-layered plasma membranes from nontreated cells, ERM proteins and actin filaments were densely detected, whereas those from FasL-treated cells were free from ERM proteins or actin filaments. We thus concluded that the cytoplasmic translocation of ERM proteins is responsible for the microvillar breakdown at an early phase of apoptosis and that the depletion of ERM proteins from plasma membranes results in the gross dissociation of actin-based cytoskeleton from plasma membranes. The physiological relevance of this ERM protein–based microvillar breakdown in apoptosis will be discussed.

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Yonemura, Shigenobu, Takeshi Matsui, Shoichiro Tsukita, and Sachiko Tsukita. "Rho-dependent and -independent activation mechanisms of ezrin/radixin/moesin proteins: an essential role for polyphosphoinositides in vivo." Journal of Cell Science 115, no. 12 (June 15, 2002): 2569–80. http://dx.doi.org/10.1242/jcs.115.12.2569.

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Ezrin/radixin/moesin (ERM) proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton,especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine-phosphorylated ERM proteins (CPERMs). Using a CPERM-specific mAb, we have shown, in vivo, that treatment with C3 transferase (a Rho inactivator) or staurosporine (a protein kinase inhibitor) leads to the dephosphorylation of CPERMs, the translocation of ERM proteins from plasma membranes to the cytoplasm and microvillar breakdown. We further elucidated that ERM protein activation does not require C-terminal phosphorylation in A431 cells stimulated with epidermal growth factor. In certain types of kidney-derived cells such as MDCK cells, however, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Interestingly, microinjection of an aminoglycoside antibiotic, neomycin, which binds to polyphosphoinositides, such as phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2],affected the activation of ERM proteins regardless of cell type. These findings not only indicate the existence of a Rho-independent activation mechanism of ERM proteins but also suggest that both Rho-dependent and-independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo.

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Hirao, M., N. Sato, T. Kondo, S. Yonemura, M. Monden, T. Sasaki, Y. Takai, S. Tsukita, and S. Tsukita. "Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway." Journal of Cell Biology 135, no. 1 (October 1, 1996): 37–51. http://dx.doi.org/10.1083/jcb.135.1.37.

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The ERM proteins, ezrin, radixin, and moesin, are involved in the actin filament/plasma membrane interaction as cross-linkers. CD44 has been identified as one of the major membrane binding partners for ERM proteins. To examine the CD44/ERM protein interaction in vitro, we produced mouse ezrin, radixin, moesin, and the glutathione-S-transferase (GST)/CD44 cytoplasmic domain fusion protein (GST-CD44cyt) by means of recombinant baculovirus infection, and constructed an in vitro assay for the binding between ERM proteins and the cytoplasmic domain of CD44. In this system, ERM proteins bound to GST-CD44cyt with high affinity (Kd of moesin was 9.3 +/- 1.6nM) at a low ionic strength, but with low affinity at a physiological ionic strength. However, in the presence of phosphoinositides (phosphatidylinositol [PI], phosphatidylinositol 4-monophosphate [4-PIP], and phosphatidylinositol 4.5-bisphosphate [4,5-PIP2]), ERM proteins bound with a relatively high affinity to GST-CD44cyt even at a physiological ionic strength: 4,5-PIP2 showed a marked effect (Kd of moesin in the presence of 4,5-PIP2 was 9.3 +/- 4.8 nM). Next, to examine the regulation mechanism of CD44/ERM interaction in vivo, we reexamined the immunoprecipitated CD44/ERM complex from BHK cells and found that it contains Rho-GDP dissociation inhibitor (GDI), a regulator of Rho GTPase. We then evaluated the involvement of Rho in the regulation of the CD44/ERM complex formation. When recombinant ERM proteins were added and incubated with lysates of cultured BHK cells followed by centrifugation, a portion of the recombinant ERM proteins was recovered in the insoluble fraction. This binding was enhanced by GTP gamma S and markedly suppressed by C3 toxin, a specific inhibitor of Rho, indicating that the GTP form of Rho in the lysate is required for this binding. A mAb specific for the cytoplasmic domain of CD44 also markedly suppressed this binding, identifying most of the binding partners for exogenous ERM proteins in the insoluble fraction as CD44. Consistent with this binding analysis, in living BHK cells treated with C3 toxin, most insoluble ERM proteins moved to soluble compartments in the cytoplasm, leaving CD44 free from ERM. These findings indicate that Rho regulates the CD44/ERM complex formation in vivo and that the phosphatidylinositol turnover may be involved in this regulation mechanism.

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Yonemura, Shigenobu, Sachiko Tsukita, and Shoichiro Tsukita. "Direct Involvement of Ezrin/Radixin/Moesin (ERM)-binding Membrane Proteins in the Organization of Microvilli in Collaboration with Activated ERM Proteins." Journal of Cell Biology 145, no. 7 (June 28, 1999): 1497–509. http://dx.doi.org/10.1083/jcb.145.7.1497.

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Ezrin/radixin/moesin (ERM) proteins have been thought to play a central role in the organization of cortical actin-based cytoskeletons including microvillar formation through cross-linking actin filaments and integral membrane proteins such as CD43, CD44, and ICAM-2. To examine the functions of these ERM-binding membrane proteins (ERMBMPs) in cortical morphogenesis, we overexpressed ERMBMPs (the extracellular domain of E-cadherin fused with the transmembrane/cytoplasmic domain of CD43, CD44, or ICAM-2) in various cultured cells. In cultured fibroblasts such as L and CV-1 cells, their overexpression significantly induced microvillar elongation, recruiting ERM proteins and actin filaments. When the ERM-binding domains were truncated from these molecules, their ability to induce microvillar elongation became undetectable. In contrast, in cultured epithelial cells such as MTD-1A and A431 cells, the overexpression of ERMBMPs did not elongate microvilli. However, in the presence of EGF, overexpression of ERMBMPs induced remarkable microvillar elongation in A431 cells. These results indicated that ERMBMPs function as organizing centers for cortical morphogenesis by organizing microvilli in collaboration with activated ERM proteins. Furthermore, immunodetection with a phosphorylated ERM-specific antibody and site-directed mutagenesis suggested that ERM proteins phosphorylated at their COOH-terminal threonine residue represent activated ERM proteins.

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Michie, Katharine A., Adam Bermeister, Neil O. Robertson, Sophia C. Goodchild, and Paul M. G. Curmi. "Two Sides of the Coin: Ezrin/Radixin/Moesin and Merlin Control Membrane Structure and Contact Inhibition." International Journal of Molecular Sciences 20, no. 8 (April 23, 2019): 1996. http://dx.doi.org/10.3390/ijms20081996.

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The merlin-ERM (ezrin, radixin, moesin) family of proteins plays a central role in linking the cellular membranes to the cortical actin cytoskeleton. Merlin regulates contact inhibition and is an integral part of cell–cell junctions, while ERM proteins, ezrin, radixin and moesin, assist in the formation and maintenance of specialized plasma membrane structures and membrane vesicle structures. These two protein families share a common evolutionary history, having arisen and separated via gene duplication near the origin of metazoa. During approximately 0.5 billion years of evolution, the merlin and ERM family proteins have maintained both sequence and structural conservation to an extraordinary level. Comparing crystal structures of merlin-ERM proteins and their complexes, a picture emerges of the merlin-ERM proteins acting as switchable interaction hubs, assembling protein complexes on cellular membranes and linking them to the actin cytoskeleton. Given the high level of structural conservation between the merlin and ERM family proteins we speculate that they may function together.

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Adyshev, Djanybek M., Steven M. Dudek, Nurgul Moldobaeva, Kyung-mi Kim, Shwu-Fan Ma, Anita Kasa, Joe G. N. Garcia, and Alexander D. Verin. "Ezrin/radixin/moesin proteins differentially regulate endothelial hyperpermeability after thrombin." American Journal of Physiology-Lung Cellular and Molecular Physiology 305, no. 3 (August 1, 2013): L240—L255. http://dx.doi.org/10.1152/ajplung.00355.2012.

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Endothelial cell (EC) barrier disruption induced by inflammatory agonists such as thrombin leads to potentially lethal physiological dysfunction such as alveolar flooding, hypoxemia, and pulmonary edema. Thrombin stimulates paracellular gap and F-actin stress fiber formation, triggers actomyosin contraction, and alters EC permeability through multiple mechanisms that include protein kinase C (PKC) activation. We previously have shown that the ezrin, radixin, and moesin (ERM) actin-binding proteins differentially participate in sphingosine-1 phosphate-induced EC barrier enhancement. Phosphorylation of a conserved threonine residue in the COOH-terminus of ERM proteins causes conformational changes in ERM to unmask binding sites and is considered a hallmark of ERM activation. In the present study we test the hypothesis that ERM proteins are phosphorylated on this critical threonine residue by thrombin-induced signaling events and explore the role of the ERM family in modulating thrombin-induced cytoskeletal rearrangement and EC barrier function. Thrombin promotes ERM phosphorylation at this threonine residue (ezrin Thr567, radixin Thr564, moesin Thr558) in a PKC-dependent fashion and induces translocation of phosphorylated ERM to the EC periphery. Thrombin-induced ERM threonine phosphorylation is likely synergistically mediated by protease-activated receptors PAR1 and PAR2. Using the siRNA approach, depletion of either moesin alone or of all three ERM proteins significantly attenuates thrombin-induced increase in EC barrier permeability (transendothelial electrical resistance), cytoskeletal rearrangements, paracellular gap formation, and accumulation of phospho-myosin light chain. In contrast, radixin depletion exerts opposing effects on these indexes. These data suggest that ERM proteins play important differential roles in the thrombin-induced modulation of EC permeability, with moesin promoting barrier dysfunction and radixin opposing it.

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Tavasoli, Mahtab, Abass Al-Momany, Xin Wang, Laiji Li, John C. Edwards, and Barbara J. Ballermann. "Both CLIC4 and CLIC5A activate ERM proteins in glomerular endothelium." American Journal of Physiology-Renal Physiology 311, no. 5 (November 1, 2016): F945—F957. http://dx.doi.org/10.1152/ajprenal.00353.2016.

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The chloride intracellular channel (CLIC) 5A is expressed at very high levels in renal glomeruli, in both endothelial cells (EC) and podocytes. CLIC5A stimulates Rac1- and phosphatidylinositol (4,5)-bisphosphate-dependent ERM (ezrin, radixin, moesin) activation. ERM proteins, in turn, function in lumen formation and in the development of actin-based cellular projections. In mice lacking CLIC5A, ERM phosphorylation is profoundly reduced in podocytes, but preserved in glomerular EC. Since glomerular EC also express CLIC4, we reasoned that, if CLIC4 activates ERM proteins like CLIC5A, then CLIC4 could compensate for the CLIC5A loss in glomerular EC. In glomeruli of CLIC5-deficient mice, CLIC4 expression was upregulated and colocalized with moesin and ezrin in glomerular EC, but not in podocytes. In cultured glomerular EC, CLIC4 silencing reduced ERM phosphorylation and cytoskeletal association, and expression of exogenous CLIC4 or CLIC5A rescued ERM de-phosphorylation due to CLIC4 silencing. In mice lacking either CLIC4 or CLIC5, ERM phosphorylation was retained in glomerular EC, but, in mice lacking both CLIC4 and CLIC5, glomerular EC ERM phosphorylation was profoundly reduced. Although glomerular EC fenestrae developed normally in dual CLIC4/CLIC5-deficient mice, the density of fenestrae declined substantially by 8 mo of age, along with the deposition of subendothelial electron-lucent material. The dual CLIC4/CLIC5-deficient mice developed spontaneous proteinuria, glomerular cell proliferation, and matrix deposition. Thus CLIC4 stimulates ERM activation and can compensate for CLIC5A in glomerular EC. The findings indicate that CLIC4/CLIC5A-mediated ERM activation is required for maintenance of the glomerular capillary architecture.

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Chen, Emily, Meredith Shaffer, Verena Niggli, and Janis Burkhardt. "Flotillins and ERM proteins function to promote uropod formation in T cells (44.10)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 44.10. http://dx.doi.org/10.4049/jimmunol.184.supp.44.10.

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Abstract Migrating and adherent T cells form a protruding leading edge and a constricted tail-like structure termed the uropod. The formation of these two structures involves the segregation of specific cytoskeletal elements and cell surface molecules, including proteins that organize cell polarity in other systems. Among the proteins that are segregated to the uropod are ezrin and moesin, ERM family proteins that organize cell membrane domains by linking cytoplasmic and cytosolic proteins to the actin cytoskeleton. Using conditional ezrin-deficient mice in conjunction with siRNA for moesin, we show that ezrin and moesin are required for uropod formation. In addition to ERM proteins, we find that the lipid-raft associated actin-binding proteins flotillins/reggies are also associated with the T cell uropod. Flotillins form a polarized cap even under conditions where a constricted uropod has not formed. Suppression of flotillin expression inhibits uropod formation and the polarization of ERM proteins and their binding partners. These data support a model in which flotillins mark a cell surface domain to which ERM proteins are recruited, and ERM proteins then promote formation of a constricted uropod structure. Since flotillins are not known to interact directly with ERM proteins, intermediary molecules, such as their common binding partner, PSGL-1, may be involved.

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Robertson, Tanner Ford, Daniel Blumenthal, Vidhi Chandra, and Janis K. Burkhardt. "ERM family proteins regulate T cell signal initiation by limiting Lck activity and T cell receptor clustering." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 136.6. http://dx.doi.org/10.4049/jimmunol.198.supp.136.6.

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Abstract Ezrin, radixin, and moesin (ERM) proteins create specialized membrane subdomains by linking phosphatidyl inositol lipids and protein binding partners in the plasma membrane to the underlying actin cortex. These proteins are widely expressed and have well-characterized roles in cell polarity, development, and cytokinesis. In recent years, it has become clear that these proteins are also intimately involved in signal transduction. In humans, mutations in ERM proteins cause severe immunodeficiency characterized by lymphopenia and poor T cell proliferation. To investigate the role of ERM proteins in T cell activation, we generated mice with T cells deficient in ezrin and moesin, the two ERM family members expressed by T cells. Preliminary analysis shows that ERM-deficient CD4+ T cells proliferate poorly in vitro. Interestingly, however, these T cells signal more robustly in response to TCR ligation and produce high amounts of IFNγ. At rest, ERM-deficient T cells exhibit enhanced phosphorylation of Lck and larger pre-clustering of the T cell receptor. These data are consistent with a model in which ERM proteins both maintain cortical actin fences to limit TCR clustering and recruit negative regulators of proximal signaling events to the plasma membrane, thereby governing early events in the TCR signaling cascade.

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Gloerich, Martijn, Bas Ponsioen, Marjolein J. Vliem, Zhongchun Zhang, Jun Zhao, Matthijs R. Kooistra, Leo S. Price, et al. "Spatial Regulation of Cyclic AMP-Epac1 Signaling in Cell Adhesion by ERM Proteins." Molecular and Cellular Biology 30, no. 22 (September 20, 2010): 5421–31. http://dx.doi.org/10.1128/mcb.00463-10.

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ABSTRACT Epac1 is a guanine nucleotide exchange factor for the small G protein Rap and is involved in membrane-localized processes such as integrin-mediated cell adhesion and cell-cell junction formation. Cyclic AMP (cAMP) directly activates Epac1 by release of autoinhibition and in addition induces its translocation to the plasma membrane. Here, we show an additional mechanism of Epac1 recruitment, mediated by activated ezrin-radixin-moesin (ERM) proteins. Epac1 directly binds with its N-terminal 49 amino acids to ERM proteins in their open conformation. Receptor-induced activation of ERM proteins results in increased binding of Epac1 and consequently the clustered localization of Epac1 at the plasma membrane. Deletion of the N terminus of Epac1, as well as disruption of the Epac1-ERM interaction by an interfering radixin mutant or small interfering RNA (siRNA)-mediated depletion of the ERM proteins, impairs Epac1-mediated cell adhesion. We conclude that ERM proteins are involved in the spatial regulation of Epac1 and cooperate with cAMP- and Rap-mediated signaling to regulate adhesion to the extracellular matrix.

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Hao, Jian-Jiang, Yin Liu, Michael Kruhlak, Karen E. Debell, Barbara L. Rellahan, and Stephen Shaw. "Phospholipase C–mediated hydrolysis of PIP2 releases ERM proteins from lymphocyte membrane." Journal of Cell Biology 184, no. 3 (February 9, 2009): 451–62. http://dx.doi.org/10.1083/jcb.200807047.

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Mechanisms controlling the disassembly of ezrin/radixin/moesin (ERM) proteins, which link the cytoskeleton to the plasma membrane, are incompletely understood. In lymphocytes, chemokine (e.g., SDF-1) stimulation inactivates ERM proteins, causing their release from the plasma membrane and dephosphorylation. SDF-1–mediated inactivation of ERM proteins is blocked by phospholipase C (PLC) inhibitors. Conversely, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) levels by activation of PLC, expression of active PLC mutants, or acute targeting of phosphoinositide 5-phosphatase to the plasma membrane promotes release and dephosphorylation of moesin and ezrin. Although expression of phosphomimetic moesin (T558D) or ezrin (T567D) mutants enhances membrane association, activation of PLC still relocalizes them to the cytosol. Similarly, in vitro binding of ERM proteins to the cytoplasmic tail of CD44 is also dependent on PIP2. These results demonstrate a new role of PLCs in rapid cytoskeletal remodeling and an additional key role of PIP2 in ERM protein biology, namely hydrolysis-mediated ERM inactivation.

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Lopez, James P., Jerrold R. Turner, and Louis H. Philipson. "Glucose-induced ERM protein activation and translocation regulates insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 299, no. 5 (November 2010): E772—E785. http://dx.doi.org/10.1152/ajpendo.00199.2010.

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A key step in regulating insulin secretion is insulin granule trafficking to the plasma membrane. Using live-cell time-lapse confocal microscopy, we observed a dynamic association of insulin granules with filamentous actin and PIP2-enriched structures. We found that the scaffolding protein family ERM, comprising ezrin, radixin, and moesin, are expressed in β-cells and target both F-actin and PIP2. Furthermore, ERM proteins are activated via phosphorylation in a glucose- and calcium-dependent manner. This activation leads to a translocation of the ERM proteins to sites on the cell periphery enriched in insulin granules, the exocyst complex docking protein Exo70, and lipid rafts. ERM scaffolding proteins also participate in insulin granule trafficking and docking to the plasma membrane. Overexpression of a truncated dominant-negative ezrin construct that lacks the ERM F-actin binding domain leads to a reduction in insulin granules near the plasma membrane and impaired secretion. Conversely, overexpression of a constitutively active ezrin results in more granules near the cell periphery and an enhancement of insulin secretion. Diabetic mouse islets contain less active ERM, suggestive of a novel mechanism whereby impairment of insulin granule trafficking to the membrane through a complex containing F-actin, PIP2, Exo70, and ERM proteins contributes to defective insulin secretion.

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Gandy, K. Alexa Orr, Daniel Canals, Mohamad Adada, Masayuki Wada, Patrick Roddy, Ashley J. Snider, Yusuf A. Hannun, and Lina M. Obeid. "Sphingosine 1-phosphate induces filopodia formation through S1PR2 activation of ERM proteins." Biochemical Journal 449, no. 3 (January 9, 2013): 661–72. http://dx.doi.org/10.1042/bj20120213.

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Previously we demonstrated that the sphingolipids ceramide and S1P (sphingosine 1-phosphate) regulate phosphorylation of the ERM (ezrin/radixin/moesin) family of cytoskeletal proteins [Canals, Jenkins, Roddy, Hernande-Corbacho, Obeid and Hannun (2010) J. Biol. Chem. 285, 32476–3285]. In the present article, we show that exogenously applied or endogenously generated S1P (in a sphingosine kinase-dependent manner) results in significant increases in phosphorylation of ERM proteins as well as filopodia formation. Using phosphomimetic and non-phosphorylatable ezrin mutants, we show that the S1P-induced cytoskeletal protrusions are dependent on ERM phosphorylation. Employing various pharmacological S1PR (S1P receptor) agonists and antagonists, along with siRNA (small interfering RNA) techniques and genetic knockout approaches, we identify the S1PR2 as the specific and necessary receptor to induce phosphorylation of ERM proteins and subsequent filopodia formation. Taken together, the results demonstrate a novel mechanism by which S1P regulates cellular architecture that requires S1PR2 and subsequent phosphorylation of ERM proteins.

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Yang, Hai-Su, Kamilah Alexander, Pedro Santiago, and Philip W. Hinds. "ERM Proteins and Cdk5 in Cellular Senescence." Cell Cycle 2, no. 6 (November 28, 2003): 517–20. http://dx.doi.org/10.4161/cc.2.6.582.

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Proudfit, Austin, Nabanita Bhunia, Debasis Pore, Yvonne Parker, Daniel Lindner, and Neetu Gupta. "Pharmacologic Inhibition of Ezrin-Radixin-Moesin Phosphorylation is a Novel Therapeutic Strategy in Rhabdomyosarcoma." Sarcoma 2020 (September 9, 2020): 1–11. http://dx.doi.org/10.1155/2020/9010496.

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Intermediate and high-risk rhabdomyosarcoma (RMS) patients have poor prognosis with available treatment options, highlighting a clear unmet need for identification of novel therapeutic strategies. Ezrin-radixin-moesin (ERM) family members are membrane-cytoskeleton linker proteins with well-defined roles in tumor metastasis, growth, and survival. ERM protein activity is regulated by dynamic changes in the phosphorylation at a conserved threonine residue in their C-terminal actin-binding domain. Interestingly, ERM family member, ezrin, has elevated expression in the RMS tissue. Despite this, the translational scope of targeting ERM family proteins in these tumors through pharmacological inhibition has never been considered. This study investigates the inhibition of ERM phosphorylation using a small molecule pharmacophore NSC668394 as a potential strategy against RMS. Upon in vitro treatment with NSC668394, RMS cells exhibit a dose-dependent decrease in cell viability and proliferation, with induction of caspase-3 cleavage and apoptosis. siRNA-mediated knockdown of individual ERM protein expression revealed that each regulates RMS survival to a different degree. In vivo administration of NSC668394 in RMS xenografts causes significant decrease in tumor growth, with no adverse effect on body weight. Collectively, this study highlights the importance of the active conformation of ERM proteins in RMS progression and survival and supports pharmacologic inhibition of these proteins as a novel therapeutic approach.

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Ramalho, João J., Jorian J. Sepers, Ophélie Nicolle, Ruben Schmidt, Janine Cravo, Grégoire Michaux, and Mike Boxem. "C-terminal phosphorylation modulates ERM-1 localization and dynamics to control cortical actin organization and support lumen formation during Caenorhabditiselegans development." Development 147, no. 14 (June 25, 2020): dev188011. http://dx.doi.org/10.1242/dev.188011.

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ABSTRACTERM proteins are conserved regulators of cortical membrane specialization that function as membrane-actin linkers and molecular hubs. The activity of ERM proteins requires a conformational switch from an inactive cytoplasmic form into an active membrane- and actin-bound form, which is thought to be mediated by sequential PIP2 binding and phosphorylation of a conserved C-terminal threonine residue. Here, we use the single Caenorhabditiselegans ERM ortholog, ERM-1, to study the contribution of these regulatory events to ERM activity and tissue formation in vivo. Using CRISPR/Cas9-generated erm-1 mutant alleles, we demonstrate that a PIP2-binding site is crucially required for ERM-1 function. By contrast, dynamic regulation of C-terminal T544 phosphorylation is not essential but modulates ERM-1 apical localization and dynamics in a tissue-specific manner, to control cortical actin organization and support lumen formation in epithelial tubes. Our work highlights the dynamic nature of ERM protein regulation during tissue morphogenesis and the importance of C-terminal phosphorylation in fine-tuning ERM activity in a tissue-specific context.

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Yonemura, Shigenobu, Motohiro Hirao, Yoshinori Doi, Nobuyuki Takahashi, Takahisa Kondo, Sachiko Tsukita, and Shoichiro Tsukita. "Ezrin/Radixin/Moesin (ERM) Proteins Bind to a Positively Charged Amino Acid Cluster in the Juxta-Membrane Cytoplasmic Domain of CD44, CD43, and ICAM-2." Journal of Cell Biology 140, no. 4 (February 23, 1998): 885–95. http://dx.doi.org/10.1083/jcb.140.4.885.

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Abstract. CD44 has been identified as a membrane-binding partner for ezrin/radixin/moesin (ERM) proteins, plasma membrane/actin filament cross-linkers. ERM proteins, however, are not necessarily colocalized with CD44 in tissues, but with CD43 and ICAM-2 in some types of cells. We found that glutathione-S-transferase fusion proteins with the cytoplasmic domain of CD43 and ICAM-2, as well as CD44, bound to moesin in vitro. The regions responsible for the in vitro binding of CD43 and CD44 to moesin were narrowed down to their juxta-membrane 20–30–amino acid sequences in the cytoplasmic domain. These sequences and the cytoplasmic domain of ICAM-2 (28 amino acids) were all characterized by the positively charged amino acid clusters. When E-cadherin chimeric molecules bearing these positively charged amino acid clusters of CD44, CD43, or ICAM-2 were expressed in mouse L fibroblasts, they were co-concentrated with ERM proteins at microvilli, whereas those lacking these clusters were diffusely distributed on the cell surface. The specific binding of ERM proteins to the juxta-membrane positively charged amino acid clusters of CD44, CD43, and ICAM-2 was confirmed by immunoprecipitation and site-directed mutagenesis. From these findings, we conclude that ERM proteins bind to integral membrane proteins bearing a positively charged amino acid cluster in their juxta-membrane cytoplasmic domain.

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Dickson, Tracey C., C. David Mintz, Deanna L. Benson, and Stephen R. J. Salton. "Functional binding interaction identified between the axonal CAM L1 and members of the ERM family." Journal of Cell Biology 157, no. 7 (June 17, 2002): 1105–12. http://dx.doi.org/10.1083/jcb.200111076.

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Ayeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane–cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM–actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis.

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Treanor, Bebhinn, David Depoil, Andreas Bruckbauer, and Facundo D. Batista. "Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity." Journal of Experimental Medicine 208, no. 5 (April 11, 2011): 1055–68. http://dx.doi.org/10.1084/jem.20101125.

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Signaling microclusters are a common feature of lymphocyte activation. However, the mechanisms controlling the size and organization of these discrete structures are poorly understood. The Ezrin-Radixin-Moesin (ERM) proteins, which link plasma membrane proteins with the actin cytoskeleton and regulate the steady-state diffusion dynamics of the B cell receptor (BCR), are transiently dephosphorylated upon antigen receptor stimulation. In this study, we show that the ERM proteins ezrin and moesin influence the organization and integrity of BCR microclusters. BCR-driven inactivation of ERM proteins is accompanied by a temporary increase in BCR diffusion, followed by BCR immobilization. Disruption of ERM protein function using dominant-negative or constitutively active ezrin constructs or knockdown of ezrin and moesin expression quantitatively and qualitatively alters BCR microcluster formation, antigen aggregation, and downstream BCR signal transduction. Chemical inhibition of actin polymerization also altered the structure and integrity of BCR microclusters. Together, these findings highlight a crucial role for the cortical actin cytoskeleton during B cell spreading and microcluster formation and function.

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Chirivino, Dafne, Laurence Del Maestro, Etienne Formstecher, Philippe Hupé, Graça Raposo, Daniel Louvard, and Monique Arpin. "The ERM proteins interact with the HOPS complex to regulate the maturation of endosomes." Molecular Biology of the Cell 22, no. 3 (February 2011): 375–85. http://dx.doi.org/10.1091/mbc.e10-09-0796.

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In the degradative pathway, the progression of cargos through endosomal compartments involves a series of fusion and maturation events. The HOPS (homotypic fusion and protein sorting) complex is part of the machinery that promotes the progression from early to late endosomes and lysosomes by regulating the exchange of small GTPases. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. This impairment in EGFR trafficking observed in cells depleted of ERM proteins is due to a delay in the recruitment of Rab7 on endosomes. As a consequence, the maturation of endosomes is perturbed as reflected by an accumulation of hybrid compartments positive for both early and late endosomal markers. Thus, ERM proteins represent novel regulators of the HOPS complex in the early to late endosomal maturation.

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Asano, Shinji. "Functional Regulation of Transport Proteins by ERM (Ezrin / Radixin / Moesin) Proteins." membrane 35, no. 6 (2010): 278–84. http://dx.doi.org/10.5360/membrane.35.278.

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Kobori, Takuro, Mayuka Tameishi, Chihiro Tanaka, Yoko Urashima, and Tokio Obata. "Subcellular distribution of ezrin/radixin/moesin and their roles in the cell surface localization and transport function of P-glycoprotein in human colon adenocarcinoma LS180 cells." PLOS ONE 16, no. 5 (May 11, 2021): e0250889. http://dx.doi.org/10.1371/journal.pone.0250889.

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The ezrin/radixin/moesin (ERM) family proteins act as linkers between the actin cytoskeleton and P-glycoprotein (P-gp) and regulate the plasma membrane localization and functionality of the latter in various cancer cells. Notably, P-gp overexpression in the plasma membrane of cancer cells is a principal factor responsible for multidrug resistance and drug-induced mutagenesis. However, it remains unknown whether the ERM proteins contribute to the plasma membrane localization and transport function of P-gp in human colorectal cancer cells in which the subcellular localization of ERM has yet to be determined. This study aimed to determine the gene expression patterns and subcellular localization of ERM and P-gp and investigate the role of ERM proteins in the plasma membrane localization and transport function of P-gp using the human colon adenocarcinoma cell line LS180. Using real-time reverse transcription polymerase chain reaction and immunofluorescence analyses, we showed higher levels of ezrin and moesin mRNAs than those of radixin mRNA in these cells and preferential distribution of all three ERM proteins on the plasma membrane. The ERM proteins were highly colocalized with P-gp. Additionally, we show that the knockdown of ezrin, but not of radixin and moesin, by RNA interference significantly decreased the cell surface expression of P-gp in LS180 cells without affecting the mRNA expression of P-gp. Furthermore, gene silencing of ezrin substantially increased the intracellular accumulation of rhodamine123, a typical P-gp substrate, with no alterations in the plasma membrane permeability of Evans blue, a passive transport marker. In conclusion, ezrin may primarily regulate the cell surface localization and transport function of P-gp as a scaffold protein without influencing the transcriptional activity of P-gp in LS180 cells. These findings should be relevant for treating colorectal cancer, which is the second leading cause of cancer-related deaths in males and females combined.

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Rasmussen, Maria, R. Todd Alexander, Barbara V. Darborg, Nadja Møbjerg, Else K. Hoffmann, András Kapus, and Stine F. Pedersen. "Osmotic cell shrinkage activates ezrin/radixin/moesin (ERM) proteins: activation mechanisms and physiological implications." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C197—C212. http://dx.doi.org/10.1152/ajpcell.00268.2007.

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Hyperosmotic shrinkage induces multiple cellular responses, including activation of volume-regulatory ion transport, cytoskeletal reorganization, and cell death. Here we investigated the possible roles of ezrin/radixin/moesin (ERM) proteins in these events. Osmotic shrinkage of Ehrlich Lettre ascites cells elicited the formation of long microvillus-like protrusions, rapid translocation of endogenous ERM proteins and green fluorescent protein-tagged ezrin to the cortical region including these protrusions, and Thr567/564/558 (ezrin/radixin/moesin) phosphorylation of cortical ERM proteins. Reduced cell volume appeared to be the critical parameter in hypertonicity-induced ERM protein activation, whereas alterations in extracellular ionic strength or intracellular pH were not involved. A shrinkage-induced increase in the level of membrane-associated phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] appeared to play an important role in ERM protein activation, which was prevented after PtdIns(4,5)P2 depletion by expression of the synaptojanin-2 phosphatase domain. While expression of constitutively active RhoA increased basal ERM phosphorylation, the Rho-Rho kinase pathway did not appear to be involved in shrinkage-induced ERM protein phosphorylation, which was also unaffected by the inhibition or absence of Na+/H+ exchanger isoform (NHE1). Ezrin knockdown by small interfering RNA increased shrinkage-induced NHE1 activity, reduced basal and shrinkage-induced Rho activity, and attenuated the shrinkage-induced formation of microvillus-like protrusions. Hyperosmolarity-induced cell death was unaltered by ezrin knockdown or after phosphatidylinositol 3-kinase (PI3K) inhibition. In conclusion, ERM proteins are activated by osmotic shrinkage in a PtdIns(4,5)P2-dependent, NHE1-independent manner. This in turn mitigates the shrinkage-induced activation of NHE1, augments Rho activity, and may also contribute to F-actin rearrangement. In contrast, no evidence was found for the involvement of an NHE1-ezrin-PI3K-PKB pathway in counteracting shrinkage-induced cell death.

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Matsui, Takeshi, Masato Maeda, Yoshinori Doi, Shigenobu Yonemura, Mutsuki Amano, Kozo Kaibuchi, Sachiko Tsukita, and Shoichiro Tsukita. "Rho-Kinase Phosphorylates COOH-terminal Threonines of Ezrin/Radixin/Moesin (ERM) Proteins and Regulates Their Head-to-Tail Association." Journal of Cell Biology 140, no. 3 (February 9, 1998): 647–57. http://dx.doi.org/10.1083/jcb.140.3.647.

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The ezrin/radixin/moesin (ERM) proteins are involved in actin filament/plasma membrane interaction that is regulated by Rho. We examined whether ERM proteins are directly phosphorylated by Rho- associated kinase (Rho-kinase), a direct target of Rho. Recombinant full-length and COOH-terminal half radixin were incubated with constitutively active catalytic domain of Rho-kinase, and ∼30 and ∼100% of these molecules, respectively, were phosphorylated mainly at the COOH-terminal threonine (T564). Next, to detect Rho-kinase–dependent phosphorylation of ERM proteins in vivo, we raised a mAb that recognized the T564-phosphorylated radixin as well as ezrin and moesin phosphorylated at the corresponding threonine residue (T567 and T558, respectively). Immunoblotting of serum-starved Swiss 3T3 cells with this mAb revealed that after LPA stimulation ERM proteins were rapidly phosphorylated at T567 (ezrin), T564 (radixin), and T558 (moesin) in a Rho-dependent manner and then dephosphorylated within 2 min. Furthermore, the T564 phosphorylation of recombinant COOH-terminal half radixin did not affect its ability to bind to actin filaments in vitro but significantly suppressed its direct interaction with the NH2-terminal half of radixin. These observations indicate that the Rho-kinase–dependent phosphorylation interferes with the intramolecular and/ or intermolecular head-to-tail association of ERM proteins, which is an important mechanism of regulation of their activity as actin filament/plasma membrane cross-linkers.

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Zegers, Ingrid, Thomas Keller, Wiebke Schreiber, Joanna Sheldon, Riccardo Albertini, Søren Blirup-Jensen, Myron Johnson, et al. "Characterization of the New Serum Protein Reference Material ERM-DA470k/IFCC: Value Assignment by Immunoassay." Clinical Chemistry 56, no. 12 (December 1, 2010): 1880–88. http://dx.doi.org/10.1373/clinchem.2010.148809.

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BACKGROUND The availability of a suitable matrix reference material is essential for standardization of the immunoassays used to measure serum proteins. The earlier serum protein reference material ERM-DA470 (previously called CRM470), certified in 1993, has led to a high degree of harmonization of the measurement results. A new serum protein material has now been prepared and its suitability in term of homogeneity and stability has been verified; after characterization, the material has been certified as ERM-DA470k/IFCC. METHODS We characterized the candidate reference material for 14 proteins by applying a protocol that is considered to be a reference measurement procedure, by use of optimized immunoassays. ERM-DA470 was used as a calibrant. RESULTS For 12 proteins [α2 macroglobulin (A2M), α1 acid glycoprotein (orosomucoid, AAG), α1 antitrypsin (α1-protease inhibitor, AAT), albumin (ALB), complement 3c (C3c), complement 4 (C4), haptoglobin (HPT), IgA, IgG, IgM, transferrin (TRF), and transthyretin (TTR)], the results allowed assignment of certified values in ERM-DA470k/IFCC. For CRP, we observed a bias between the lyophilized and liquid frozen materials, and for CER, the distribution of values was too broad. Therefore, these 2 proteins were not certified in the ERM-DA470k/IFCC. Different value transfer procedures were tested (open and closed procedures) and found to provide equivalent results. CONCLUSIONS A new serum protein reference material has been produced, and values have been successfully assigned for 12 proteins.

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Winckler, B., C. Gonzalez Agosti, M. Magendantz, and F. Solomon. "Analysis of a cortical cytoskeletal structure: a role for ezrin-radixin-moesin (ERM proteins) in the marginal band of chicken erythrocytes." Journal of Cell Science 107, no. 9 (September 1, 1994): 2523–34. http://dx.doi.org/10.1242/jcs.107.9.2523.

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We are studying how the cytoskeleton determines cell shape, using a simple model system, the marginal band of chicken erythrocytes. We previously identified a minor component of the marginal band by a monoclonal antibody, called 13H9 (Birgbauer and Solomon (1989). J. Cell Biol. 109, 1609–1620; Goslin et al. (1989). J. Cell Biol. 109, 1621–1631). mAb 13H9 also binds to the leading edges of fibroblasts and to neuronal growth cones and recognizes the cytoskeletal protein ezrin. In recent years, two proteins with a high degree of homology to ezrin were identified: moesin and radixin, together comprising the ERM protein family. We now show that the contiguous epitope sufficient for mAb 13H9 binding is a sequence present in each of the ERM proteins, as well as the product of the gene associated with neurofibromatosis 2, merlin or schwannomin. We used biochemical and immunological techniques, as well as PCR to characterize the expression and localization of the ERM proteins in chicken erythrocytes. The results demonstrate that radixin is the major ERM protein associated with the cytoskeleton. Both ezrin and radixin localize to the position of the marginal band. Our results suggest that the ERM proteins play functionally conserved roles in quite diverse organelles.

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Baeyens, Nicolas, Sandrine Horman, Didier Vertommen, Mark Rider, and Nicole Morel. "Identification and functional implication of a Rho kinase-dependent moesin-EBP50 interaction in noradrenaline-stimulated artery." American Journal of Physiology-Cell Physiology 299, no. 6 (December 2010): C1530—C1540. http://dx.doi.org/10.1152/ajpcell.00175.2010.

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Ezrin, radixin, and moesin (ERM) proteins are known to be substrates of Rho kinase (ROCK), a key player in vascular smooth muscle regulation. Their function in arteries remains to be elucidated. The objective of the present study was to investigate ERM phosphorylation and function in rat aorta and mesenteric artery and the influence of ERM-binding phosphoprotein 50 (EBP50), a scaffold partner of ERM proteins in several cell types. In isolated arteries, ERM proteins are phosphorylated by PKC and ROCK with different kinetics after either agonist stimulation or KCl-induced depolarization. Immunoprecipitation of EBP50 in noradrenaline-stimulated arteries allowed identification of its interaction with moesin and several other proteins involved in cytoskeleton regulation. This interaction was inhibited by Y27632, a ROCK inhibitor. Moesin or EBP50 depletion after small interfering RNA transfection by reverse permeabilization in intact mesenteric arteries both potentiated the contractility in response to agonist stimulation without any effect on contractile response induced by high KCl. This effect was preserved in ionomycin-permeabilized arteries. These results indicate that, in agonist-stimulated arteries, the activation of ROCK leads to the binding of moesin to EBP50, which interacts with several components of the cytoskeleton, resulting in a decrease in the contractile response.

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Cannon, J. L., P. D. Mody, K. M. Blaine, E. J. Chen, A. D. Nelson, L. J. Sayles, T. V. Moore, et al. "CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation." Molecular Biology of the Cell 22, no. 7 (April 2011): 954–63. http://dx.doi.org/10.1091/mbc.e10-07-0586.

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Cell polarization is a key feature of cell motility, driving cell migration to tissues. CD43 is an abundantly expressed molecule on the T-cell surface that shows distinct localization to the migrating T-cell uropod and the distal pole complex (DPC) opposite the immunological synapse via association with the ezrin-radixin-moesin (ERM) family of actin regulatory proteins. CD43 regulates multiple T-cell functions, including T-cell activation, proliferation, apoptosis, and migration. We recently demonstrated that CD43 regulates T-cell trafficking through a phosphorylation site at Ser-76 (S76) within its cytoplasmic tail. Using a phosphorylation-specific antibody, we now find that CD43 phosphorylation at S76 is enhanced by migration signals. We further show that CD43 phosphorylation and normal T-cell trafficking depend on CD43 association with ERM proteins. Interestingly, mutation of S76 to mimic phosphorylation enhances T-cell migration and CD43 movement to the DPC while blocking ERM association, showing that CD43 movement can occur in the absence of ERM binding. We also find that protein kinase Cθ can phosphorylate CD43. These results show that while CD43 binding to ERM proteins is crucial for S76 phosphorylation, CD43 movement and regulation of T-cell migration can occur through an ERM-independent, phosphorylation–dependent mechanism.

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Mori, T., K. Kitano, S. Terawaki, R. Maesaki, Y. Fukami, and T. Hakoshima. "Structural basis for CD44 recognition by ERM proteins." Acta Crystallographica Section A Foundations of Crystallography 64, a1 (August 23, 2008): C233—C234. http://dx.doi.org/10.1107/s0108767308092490.

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Terawaki, Shin-ichi, Ryoko Maesaki, and Toshio Hakoshima. "Structural Basis for NHERF Recognition by ERM Proteins." Structure 14, no. 4 (April 2006): 777–89. http://dx.doi.org/10.1016/j.str.2006.01.015.

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Louvet-Vallée, Sophie. "ERM proteins: From cellular architecture to cell signaling." Biology of the Cell 92, no. 5 (August 2000): 305–16. http://dx.doi.org/10.1016/s0248-4900(00)01078-9.

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Mangeat, Paul, Christian Roy, and Marianne Martin. "ERM proteins in cell adhesion and membrane dynamics." Trends in Cell Biology 9, no. 5 (May 1999): 187–92. http://dx.doi.org/10.1016/s0962-8924(99)01544-5.

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Fiévet, Bruno, Daniel Louvard, and Monique Arpin. "ERM proteins in epithelial cell organization and functions." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1773, no. 5 (May 2007): 653–60. http://dx.doi.org/10.1016/j.bbamcr.2006.06.013.

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Mori, Tomoyuki, Ken Kitano, Shin-ichi Terawaki, Ryoko Maesaki, Yayoi Fukami, and Toshio Hakoshima. "Structural Basis for CD44 Recognition by ERM Proteins." Journal of Biological Chemistry 283, no. 43 (August 27, 2008): 29602–12. http://dx.doi.org/10.1074/jbc.m803606200.

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Mintz, C. David, Ioana Carcea, Daniel G. McNickle, Tracey C. Dickson, Yongchao Ge, Stephen R. J. Salton, and Deanna L. Benson. "ERM proteins regulate growth cone responses to Sema3A." Journal of Comparative Neurology 510, no. 4 (October 1, 2008): 351–66. http://dx.doi.org/10.1002/cne.21799.

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Brown, Martin J., Ruchika Nijhara, John A. Hallam, Michelle Gignac, Kenneth M. Yamada, Stanley L. Erlandsen, Jérôme Delon, Michael Kruhlak, and Stephen Shaw. "Chemokine stimulation of human peripheral blood T lymphocytes induces rapid dephosphorylation of ERM proteins, which facilitates loss of microvilli and polarization." Blood 102, no. 12 (December 1, 2003): 3890–99. http://dx.doi.org/10.1182/blood-2002-12-3807.

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Abstract Lymphocyte microvilli mediate initial rolling-adhesion along endothelium but are lost during transmigration from circulation to tissue. However, the mechanism for resorption of lymphocyte microvilli remains unexplored. We show that chemokine stimulation of human peripheral blood T (PBT) cells is sufficient to induce rapid resorption of microvilli. Microvilli in other cells are regulated by ezrin/radixin/moesin (ERM) proteins, which link the plasma membrane to the cortical F-actin cytoskeleton; maintenance of these linkages requires ERM activation, reflected by phosphorylation at a specific carboxy-terminal threonine residue. Carboxyphosphorylated-ERM (cpERM) proteins in resting PBT cells show a punctate peripheral distribution consistent with localization to microvilli. cpERM dephosphorylation begins within seconds of stimulation by chemokines (stromal derived factor 1α [SDF-1α] or secondary lymphoid tissue cytokine), and ERM proteins lose their punctate distribution with kinetics paralleling the loss of microvilli. The cpERM proteins are preferentially associated with the cytoskeleton at rest and this association is lost with chemokine-induced dephosphorylation. Transfection studies show that a dominant-negative ERM construct destroys microvilli, whereas a construct mimicking cpERM facilitates formation of microvilli, retards chemokine-induced loss of microvilli, and markedly impairs chemokine-induced polarization. Thus, chemokine induces rapid dephosphorylation and inactivation of cpERM, which may in turn facilitate 2 aspects of cytoskeletal reorganization involved in lymphocyte recruitment: loss of microvilli and polarization.

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Hayashi, K., S. Yonemura, T. Matsui, and S. Tsukita. "Immunofluorescence detection of ezrin/radixin/moesin (ERM) proteins with their carboxyl-terminal threonine phosphorylated in cultured cells and tissues." Journal of Cell Science 112, no. 8 (April 15, 1999): 1149–58. http://dx.doi.org/10.1242/jcs.112.8.1149.

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Ezrin/radixin/moesin (ERM) proteins are thought to play an important role in organizing cortical actin-based cytoskeletons through cross-linkage of actin filaments with integral membrane proteins. Recent in vitro biochemical studies have revealed that ERM proteins phosphorylated on their COOH-terminal threonine residue (CPERMs) are active in their cross-linking activity, but this has not yet been evaluated in vivo. To immunofluorescently visualize CPERMs in cultured cells as well as tissues using a mAb specific for CPERMs, we developed a new fixation protocol using trichloroacetic acid (TCA) as a fixative. Immunoblotting analyses in combination with immunofluorescence microscopy showed that TCA effectively inactivated soluble phosphatases, which maintained the phosphorylation level of CPERMs during sample processing for immunofluorescence staining. Immunofluorescence microscopy with TCA-fixed samples revealed that CPERMs were exclusively associated with plasma membranes in a variety of cells and tissues, whereas total ERM proteins were distributed in both the cytoplasm and plasma membranes. Furthermore, the amounts of CPERMs were shown to be regulated in a cell and tissue type-dependent manner. These findings favored the notion that phosphorylation of the COOH-terminal threonine plays a key role in the regulation of the cross-linking activity of ERM proteins in vivo.

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Hoshi, Yutaro, Yasuo Uchida, Takashi Kuroda, Masanori Tachikawa, Pierre-Olivier Couraud, Takashi Suzuki, and Tetsuya Terasaki. "Distinct roles of ezrin, radixin and moesin in maintaining the plasma membrane localizations and functions of human blood–brain barrier transporters." Journal of Cerebral Blood Flow & Metabolism 40, no. 7 (August 14, 2019): 1533–45. http://dx.doi.org/10.1177/0271678x19868880.

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The purpose of this study was to clarify the roles of ERM proteins (ezrin/radixin/moesin) in the regulation of membrane localization and transport activity of transporters at the human blood–brain barrier (BBB). Ezrin or moesin knockdown in a human in vitro BBB model cell line (hCMEC/D3) reduced both BCRP and GLUT1 protein expression levels on the plasma membrane. Radixin knockdown reduced not only BCRP and GLUT1, but also P-gp membrane expression. These results indicate that P-gp, BCRP and GLUT1 proteins are maintained on the plasma membrane via different ERM proteins. Furthermore, moesin knockdown caused the largest decrease of P-gp and BCRP efflux activity among the ERM proteins, whereas GLUT1 influx activity was similarly reduced by knockdown of each ERM protein. To investigate how moesin knockdown reduced P-gp efflux activity without loss of P-gp from the plasma membrane, we examined the role of PKCβI. PKCβI increased P-gp phosphorylation and reduced P-gp efflux activity. Radixin and moesin proteins were detected in isolated human brain capillaries, and their protein abundances were within a 3-fold range, compared with those in hCMEC/D3 cell line. These findings may mean that ezrin, radixin and moesin maintain the functions of different transporters in different ways at the human BBB.

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Solinet, Sara, Kazi Mahmud, Shannon F. Stewman, Khaled Ben El Kadhi, Barbara Decelle, Lama Talje, Ao Ma, Benjamin H. Kwok, and Sébastien Carreno. "The actin-binding ERM protein Moesin binds to and stabilizes microtubules at the cell cortex." Journal of Cell Biology 202, no. 2 (July 15, 2013): 251–60. http://dx.doi.org/10.1083/jcb.201304052.

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Ezrin, Radixin, and Moesin (ERM) proteins play important roles in many cellular processes including cell division. Recent studies have highlighted the implications of their metastatic potential in cancers. ERM’s role in these processes is largely attributed to their ability to link actin filaments to the plasma membrane. In this paper, we show that the ERM protein Moesin directly binds to microtubules in vitro and stabilizes microtubules at the cell cortex in vivo. We identified two evolutionarily conserved residues in the FERM (4.1 protein and ERM) domains of ERMs that mediated the association with microtubules. This ERM–microtubule interaction was required for regulating spindle organization in metaphase and cell shape transformation after anaphase onset but was dispensable for bridging actin filaments to the metaphase cortex. These findings provide a molecular framework for understanding the complex functional interplay between the microtubule and actin cytoskeletons mediated by ERM proteins in mitosis and have broad implications in both physiological and pathological processes that require ERMs.

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McCartney, B. M., and R. G. Fehon. "Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin." Journal of Cell Biology 133, no. 4 (May 15, 1996): 843–52. http://dx.doi.org/10.1083/jcb.133.4.843.

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Interest in members of the protein 4.1 super-family, which includes the ezrin-radixin-moesin (ERM) group, has been stimulated recently by the discovery that the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like protein, merlin. Although many proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane proteins, the cellular functions of merlin have not been defined. To investigate the cellular and developmental functions of these proteins, we have identified and characterized Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor merlin (Dmerlin). Using specific antibodies, we show that although these proteins are frequently coexpressed in developing tissues, they display distinct subcellular localizations. While Dmoesin is observed in continuous association with the plasma membrane, as is typical for an ERM family protein, Dmerlin is found in punctuate structures at the membrane and in the cytoplasm. Investigation of Dmerlin cultured cells demonstrates that it is associated with endocytic compartments. As a result of these studies, we propose that the merlin protein has unique functions in the cell which differ from those of other ERM family members.

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Orian-Rousseau, Véronique, Helen Morrison, Alexandra Matzke, Thor Kastilan, Giuseppina Pace, Peter Herrlich, and Helmut Ponta. "Hepatocyte Growth Factor-induced Ras Activation Requires ERM Proteins Linked to Both CD44v6 and F-Actin." Molecular Biology of the Cell 18, no. 1 (January 2007): 76–83. http://dx.doi.org/10.1091/mbc.e06-08-0674.

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In several types of cells, the activation of the receptor tyrosine kinase c-Met by its ligand hepatocyte growth factor (HGF) requires the coreceptor CD44v6. The CD44 extracellular domain is necessary for c-Met autophosphorylation, whereas the intracellular domain is required for signal transduction. We have already shown that the CD44 cytoplasmic tail recruits ezrin, radixin and moesin (ERM) proteins to the complex of CD44v6, c-Met, and HGF. We have now defined the function of the ERM proteins and the step they promote in the signaling cascade. The association of ERM proteins to the coreceptor is absolutely required to mediate the HGF-dependent activation of Ras by the guanine nucleotide exchange factor Sos. The ERM proteins need, in addition, to be linked to the actin cytoskeleton to catalyze the activation of Ras. Thus, we describe here a new function of the cytoskeleton. It is part of a “signalosome” complex that organizes the activation of Ras by Sos. So far the cytoskeleton has mainly been identified as a “responder” to signal transduction. Here, we show now that F-actin acts as an “inducer” that actively organizes the signaling cascade.

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Iwase, Akira, Ruoqian Shen, Daniel Navarro, and David M. Nanus. "Direct Binding of Neutral Endopeptidase 24.11 to Ezrin/Radixin/Moesin (ERM) Proteins Competes with the Interaction of CD44 with ERM Proteins." Journal of Biological Chemistry 279, no. 12 (January 2, 2004): 11898–905. http://dx.doi.org/10.1074/jbc.m212737200.

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Phang, Juanita M., Stephen J. Harrop, Anthony P. Duff, Anna V. Sokolova, Ben Crossett, James C. Walsh, Simone A. Beckham, et al. "Structural characterization suggests models for monomeric and dimeric forms of full-length ezrin." Biochemical Journal 473, no. 18 (September 12, 2016): 2763–82. http://dx.doi.org/10.1042/bcj20160541.

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Ezrin is a member of the ERM (ezrin–radixin–moesin) family of proteins that have been conserved through metazoan evolution. These proteins have dormant and active forms, where the latter links the actin cytoskeleton to membranes. ERM proteins have three domains: an N-terminal FERM [band Four-point-one (4.1) ERM] domain comprising three subdomains (F1, F2, and F3); a helical domain; and a C-terminal actin-binding domain. In the dormant form, FERM and C-terminal domains form a stable complex. We have determined crystal structures of the active FERM domain and the dormant FERM:C-terminal domain complex of human ezrin. We observe a bistable array of phenylalanine residues in the core of subdomain F3 that is mobile in the active form and locked in the dormant form. As subdomain F3 is pivotal in binding membrane proteins and phospholipids, these transitions may facilitate activation and signaling. Full-length ezrin forms stable monomers and dimers. We used small-angle X-ray scattering to determine the solution structures of these species. As expected, the monomer shows a globular domain with a protruding helical coiled coil. The dimer shows an elongated dumbbell structure that is twice as long as the monomer. By aligning ERM sequences spanning metazoan evolution, we show that the central helical region is conserved, preserving the heptad repeat. Using this, we have built a dimer model where each monomer forms half of an elongated antiparallel coiled coil with domain-swapped FERM:C-terminal domain complexes at each end. The model suggests that ERM dimers may bind to actin in a parallel fashion.

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Hebert, A. M., B. DuBoff, J. B. Casaletto, A. B. Gladden, and A. I. McClatchey. "Merlin/ERM proteins establish cortical asymmetry and centrosome position." Genes & Development 26, no. 24 (December 15, 2012): 2709–23. http://dx.doi.org/10.1101/gad.194027.112.

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Fehon, Richard G., Andrea I. McClatchey, and Anthony Bretscher. "Organizing the cell cortex: the role of ERM proteins." Nature Reviews Molecular Cell Biology 11, no. 4 (April 2010): 276–87. http://dx.doi.org/10.1038/nrm2866.

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Journal articles on the topic 'ERM PROTEINS'

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