Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility

Ng, Tony; Parsons, Maddy; Hughes, William E.; Monypenny, James; Zicha, Daniel; Gautreau, Alexis; Arpin, Monique; Gschmeissner, Steve; Verveer, Peter J.; Bastiaens, Philippe I. H.; Parker, Peter J.

doi:10.1093/emboj/20.11.2723

Cited by 255 publications

(239 citation statements)

References 39 publications

(76 reference statements)

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“…ERM (ezrin [Ez], radixin [Rdx], moesin [Moe]) family proteins are known to be mediators between cellular scaffold (actin) and membrane structures (14) and by analogy have also been proposed to serve as anchoring proteins for PKC (15). This is in agreement with reports showing an interaction of PKC␣ with ezrin in vivo (24) and with the identification of ERM proteins as anchoring molecules for cyclic AMP-dependent kinase (11).…”

supporting

confidence: 75%

Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

Nüesch

Bär

Lachmann

et al. 2009

J Virol

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The propagation of autonomous parvoviruses is strongly dependent on the phosphorylation of the major nonstructural protein NS1 by members of the protein kinase C (PKC) family. Minute virus of mice (MVM) replication is accompanied by changes in the overall phosphorylation pattern of NS1, which is newly modified at consensus PKC sites. These changes result, at least in part, from the ability of MVM to modulate the PDK-1/PKC pathway, leading to activation and redistribution of both PDK-1 and PKC . We show that proteins of the ezrin-radixin-moesin (ERM) family are essential for virus propagation and spreading through their functions as adaptors for PKC . MVM infection led to redistribution of radixin and moesin in the cell, resulting in increased colocalization of these proteins with PKC . Radixin was found to control the PKCdriven phosphorylation of NS1 and newly synthesized capsids in vivo. Conversely, radixin phosphorylation and activation were driven by the NS1/CKII␣ complex. Altogether, these data argue for ERM proteins being both targets and modulators of parvovirus infection.

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supporting

confidence: 75%

Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

Nüesch

Bär

Lachmann

et al. 2009

J Virol

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“…In previous studies, we have shown ezrin to be an important mediator of breast cancer cell migration (Ng et al, 2001) and a number of recent articles have highlighted the significant contribution of ezrin to the clinical development of metastasis in both osteosarcoma and rhabdomyosarcoma Yu et al, 2004;Elliott et al, 2005). Mechanistically, ERM proteins have been implicated in the regulation of the Rho family of small GTPases either through inhibition of the Rho-specific GDP dissociation inhibitor RhoGDI (Takahashi et al, 1997) or through interaction with the Cdc42/Rhospecific guanine exchange factor Dbl (Vanni et al, 2004).…”

Section: Discussionmentioning

confidence: 96%

“…Activation of ERM proteins occurs by conformational changes triggered by binding of phosphatidylinositol 4,5-biphosphate (PIP 2 ) to the FERM (band 4.1, ERM) domain in the NH 2 -terminal region, termed the NH 2 -terminal ERM-associated domain (N-ERMAD) and phosphorylation of a conserved threonine residue (ezrin-T567, radixin-T564, moesin-T558) in the COOH-terminal domain, termed the COOH-terminal ERMassociated domain (C-ERMAD; Pietromonaco et al, 1998;Barret et al, 2000;Ng et al, 2001;Fievet et al, 2004). This sequence of molecular events releases the intramolecular interaction between the N-and C-termini.…”

Section: Introductionmentioning

confidence: 99%

“…This sequence of molecular events releases the intramolecular interaction between the N-and C-termini. Several kinases, including myotonic dystrophy kinase-related Cdc42-binding kinase Several kinases, including myotonic dystrophy kinase-related Cdc42-binding kinase (Nakamura et al, 2000), protein kinase C␣ (Ng et al, 2001), and Nck-interacting kinase (Baumgartner et al, 2006) have been shown to phosphorylate the conserved C-terminal threonine in ERM proteins. This second activation step of phosphorylation may restrict actin tethering by ERM proteins to specialized membrane domains, such as the protruding cell membranes, by locally unmasking the binding site for actin filaments in C-ERMAD.…”

Section: Introductionmentioning

confidence: 99%

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Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

Prag

Parsons

Keppler

et al. 2007

MBoC

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Establishment of polarized cell morphology is a critical factor for migration and requires precise spatial and temporal activation of the Rho GTPases. Here, we describe a novel role of the actin-binding ezrin/radixin/moesin (ERM)-protein ezrin to be involved in recruiting Cdc42, but not Rac1, to lipid raft microdomains, as well as the subsequent activation of this Rho GTPase and the downstream effector p21-activated kinase (PAK)1, as shown by fluorescence lifetime imaging microscopy. The establishment of a leading plasma membrane and the polarized morphology necessary for random migration are also dependent on ERM function and Cdc42 in motile breast carcinoma cells. Mechanistically, we show that the recruitment of the ERM-interacting Rho/Cdc42-specific guanine nucleotide exchange factor Dbl to the plasma membrane and to lipid raft microdomains requires the phosphorylated, active conformer of ezrin, which serves to tether the plasma membrane or its subdomains to the cytoskeleton. Together these data suggest a mechanism whereby precise spatial guanine nucleotide exchange of Cdc42 by Dbl is dependent on functional ERM proteins and is important for directional cell migration.

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“…Since alterations in adhesion forces, cell spreading and membrane tension have been reported as being responsible for defective cell migration [23][24][25][26], we tested the ability of Myo1g-deficient B cells to migrate toward a chemokine gradient. We used CXCL13 to induce migration of resting B lymphocytes over a fibronectincoated surface in a chemotaxis chamber.…”

Section: Slow B-cell Migration In Vitro and Defective Homing In Vivomentioning

confidence: 99%

Myosin 1g regulates cytoskeleton plasticity, cell migration, exocytosis, and endocytosis in B lymphocytes

et al. 2014

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Myosin 1g (Myo1g) is a hematopoietic-specific myosin expressed mainly by lymphocytes. Here, we report the localization of Myo1g in B-cell membrane compartments such as lipid rafts, microvilli, and membrane extensions formed during spreading. By using Myo1g-deficient mouse B cells, we detected abnormalities in the adhesion ability and chemokineinduced directed migration of these lymphocytes. We also assessed a role for Myo1g in phagocytosis and exocytosis processes, as these were also irregular in Myo1g-deficient B cells. Taken together, our results show that Myo1g acts as a main regulator of different membrane/cytoskeleton-dependent processes in B lymphocytes.Keywords: B lymphocyte r Chemotaxis r Cytoskeleton r Exo-endocytosis r Myosin Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMyosin I refers to a class of single-headed and actin-dependent molecular motors, which regulates a number of cellular functions, including intracellular transport, formation of cell-surface projections, regulation of the cytoskeleton, and regulation of membranerelated events, which includes exocytosis, endocytosis, and phagocytosis [1][2][3].Members of myosin I family contain a single heavy chain of 110-140 kDa [4,5], are monomeric, and do not form filaments unlike muscular/conventional myosin II. The single heavy chain is divided into the head (or motor), neck, and tail domains. The motor domain contains the ATP-binding (where ATP is adenosine triphosphate) site and the actin-binding site. This domain is Correspondence: Dr. Leopoldo Santos-Argumedo e-mail: lesantos@cinvestav.mx followed by the neck domain, which is involved in the binding of myosin light chains; molecules identified as calmodulin in vertebrate and yeast class I myosins [6]. Following the neck domain is the C-terminal tail region, which is enriched in basic residues and is involved in the binding of membrane phosphoinositides [7,8]. In humans and mice, eight different genes encode the eight heavy chains of class I myosins and are named Myo1a to Myo1h [2].Myosin 1g (Myo1g) is a vertebrate class I myosin, which is highly represented in leukocytes, according to microarray databases [9][10][11]. Immunoblot analyses of different tissues and cell lines recently identified this protein as being an exclusively hematopoietic motor protein [12,13].Mass spectrometric proteomic profiling of lymphocyte proteins indicates that Myo1g is the most abundant class I myosin * These authors contributed equally to this work. 878José L. Maravillas-Montero et al. Eur. J. Immunol. 2014. 44: 877-886 expressed by T lymphocytes [13]. Immunofluorescence assays showed that Myo1g localizes to the plasma membrane linked to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-triphosphate [14], is particularly enriched at cell-surface microvilli, and associates in an ATP-releasable manner to the actin cytoskeleton [12,13]. In addition to its localization pattern, it has been proposed that this molecula...

show abstract

Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility

Cited by 255 publications

References 39 publications

Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

Myosin 1g regulates cytoskeleton plasticity, cell migration, exocytosis, and endocytosis in B lymphocytes

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