Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Ezrin

  • Neetu Gupta
  • Mala Upadhyay
  • Michael Cheung
  • Nabanita Bhunia
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101745

Synonyms

Historical Background

The ERM family of proteins is composed of Ezrin, Radixin, and Moesin. ERM proteins regulate the linkage of cortical actin to membrane-associated proteins in cellular substructures by directly binding to both. Ezrin is the most studied of all ERM proteins and was identified as an 81 kDa substrate protein for receptor tyrosine kinase in A431 carcinoma cell lines (Hunter and Cooper 1981). Subsequently, it was purified as an 80 kDa protein from intestinal microvilli (Bretscher 1983). In an independent study, when an antibody was used against a 75 kDa synthetic peptide derived from cloned human endogenous retrovirus gag-related DNA sequence erv1, a protein named cytovilin was identified (Suni et al. 1984). It was found to be enriched in microvilli (Pakkanen and Vaheri 1989; Pakkanen et al. 1987) and identical to ezrin (Gould et al. 1989).

Structure, Expression, and Conformational Regulation

Gene and Domain Organization

Human ezrin gene was cloned and sequenced in 1989 (Gould et al. 1989) and shares 96% identity with the mouse ezrin gene, which was cloned and sequenced in 1991 (Funayama et al. 1991). The ezrin gene is located on chromosome 6 with 13 exons in humans, and on chromosome 17 with 13 exons in mice. The encoded protein consists of 586 amino acids, has an isoelectric point of 6.1, and is highly charged (38.5%), explaining the difference between the predicted (69 kDa) and observed (81 kDa) molecular weight. The N-terminal domain of ezrin (Fig. 1a) is highly conserved throughout the ERM family of proteins and across mammals to nematodes. Moreover, it shares ∼30% identity with band 4.1, an erythrocyte membrane protein, and therefore has been termed as the FERM (Four.one, Ezrin, Radixin, Moesin) domain (Chishti et al. 1998). The protease resistant N-terminal domain is followed by a less conserved rod-like α-helical domain and a C-terminal domain. The FERM domain binds to transmembrane and adaptor proteins whereas the C-terminal domain binds to filamentous actin (F-actin), thereby linking the plasma membrane to the cortical actin cytoskeleton.
Ezrin, Fig. 1

Domain organization and conformational activation of ezrin. (a) Ezrin consists of a highly conserved N-terminal FERM domain followed by a α-helical domain and C-terminal actin-binding domain. Serine, threonine, and tyrosine phosphorylation sites are indicated. (b) In the dormant conformation of ezrin, the FERM domain is tightly bound to the C-terminal and masks the F-actin binding sites. Upon interaction with PIP2 and phosphorylation of Thr567, ezrin undergoes conformational activation whereby it binds to transmembrane proteins and F-actin

Conformation and Regulation

Ezrin has been proposed to exist as a monomer, dimer, or oligomer depending upon its active/inactive state. In the monomeric form, the N-terminal FERM domain associates with the C-terminal actin-binding domain in an intramolecular interaction, masks the actin binding site, and hence forms the inactive or dormant state (Gary and Bretscher 1995). The active form of the protein is differentially exhibited as parallel or antiparallel dimers or head-to-tail oligomers. The coiled-coil structure of the α-helical domain has been proposed as a factor for ezrin dimerization (Bretscher et al. 1995). This idea is supported by the observation in A431 cells that EGF administration induces dimerization of ezrin and its rearrangement in microvilli. Moreover, experiments in placental villi have also revealed the existence of both dimeric and oligomeric forms (Berryman et al. 1995).

The various activities of ezrin are dependent on its phosphorylation at different amino acid residues located in the N and C-termini. Phosphorylation of threonine residue T567 at the C-terminal is essential for suppression of N-C terminal interaction, and hence activation of the protein (Matsui et al. 1998). The schematic in Fig. 1b illustrates activation and inactivation of ezrin. The tyrosine residues Y145 and Y353 in the N-terminal and α-helical domains, respectively, are important for signal transduction (Krieg and Hunter 1992). Also, serine 66 phosphorylation of ezrin by protein kinase A is associated with acid secretion by gastric parietal cells (Zhou et al. 2003). Many kinases have been proposed to phosphorylate threonine residue in various contexts, for example, Rho-associated kinase (ROCK), Cdc42-binding kinase, and protein kinase C (Oshiro et al. 1998; Nakamura et al. 2000; Pietromonaco et al. 1998). In lymphocytes, lymphocyte-oriented kinase (LOK) has been reported to phosphorylate the T567 residue (Belkina et al. 2009). Events associated with inactivation of ezrin by dephosphorylation have not been explored extensively. Nevertheless, dephosphorylation has been cited as a mechanism of inactivation which results in the translocation of ezrin to the cytosol and simultaneous breakdown of microvilli.

Communication with Cytoskeleton and Other Proteins

Ezrin is ubiquitously expressed but shows prominent localization in epithelial cells (Berryman et al. 1993) of kidney, lung, abdomen, and intestine. At the subcellular level, it is mainly confined to membrane microvilli, filopodia, uropod, and lamellopodia but some cytoplasmic ezrin is detectable in lymphocytes (Amieva et al. 1994). Immunoprecipitation studies suggested ezrin’s interaction with CD44 (Tsukita et al. 1994) and it was shown that PIP2 is required for this interaction. Through its N-terminus ezrin also binds to ICAM-2 (Helander et al. 1996), syndecan-2 (Granes et al. 2000), ezrin-binding phosphoprotein of 50 kDa (EBP50) (Reczek et al. 1997), and Rho-GDI (Takahashi et al. 1997). The C-terminal domain of ezrin has a binding site for F-actin and displays more binding affinity toward ß-actin than α-actin (Yao et al. 1996). Two additional binding sites for actin were mapped to amino acids 13–30 (Martin et al. 1997) and 288–310 (Roy et al. 1997). In parietal cells, protein kinase A subunit II binds to ezrin (Dransfield et al. 1997). The Y353 phosphorylation of ezrin results in binding to the C-terminal SH2 domain of the p85 subunit of phosphoinositde 3-kinase (PI3K) (Gautreau et al. 1999).

Role in Immune Cell Function

B Cell Immunity

B lymphocytes mediate humoral immunity by secretion of antibodies which recognize specific pathogenic organisms or molecules. In order to produce an effective response, B cells must be activated via binding of the B cell antigen receptor (BCR) to an antigen. Maintaining readiness while preventing aberrant activation and autoimmunity involves the sequestering of the BCR into distinct cell surface compartments (Treanor et al. 2010). In the absence of activation, the BCR is trapped within surface compartments created by anchoring of plasma membrane to the actin cytoskeleton by ezrin, which restricts its diffusion (Fig. 2a) (Treanor et al. 2010). B cell activation occurs when the BCR becomes crosslinked by antigen, leading to its patching, capping, and ultimately internalization. This lateral movement of the BCR on the cell surface has been associated with dynamic deactivation and activation of ezrin (Fig. 2a). Upon binding of the BCR to an antigen ezrin is dephosphorylated, assuming an inactive conformation in which N- and C-terminal domains interact (Gary and Bretscher 1995), and dissociates from lipid rafts thus permitting the coalescence of lipid rafts and BCR aggregation required for activation of B cell responses (Fig. 2a) (Gupta et al. 2006). Blocking this deactivation with phosphatase inhibitors or the expression of a constitutively active mutant of ezrin leads to a reduction in BCR signaling and lipid raft coalescence (Gupta et al. 2006). Conversely, the expression of a mutant ezrin lacking the actin-binding domain increases BCR diffusion (Treanor et al. 2011) and B cell-specific knockout of ezrin leads to increased BCR signaling, B cell proliferation, and antibody secretion (Pore et al. 2013). Expression of either the active or inactive mutants of ezrin decreases ERK phosphorylation after antigen binding, demonstrating the importance of dynamic dephosphorylation and rephosphorylation of ezrin at T567 in the regulation of BCR diffusion, clustering, and signaling. In addition to antigen, ezrin regulates B cell response to lipopolysaccharide (LPS). Similar to the BCR, toll-like receptor 4 (TLR4) engagement by LPS leads to dephosphorylation of ezrin (Parameswaran et al. 2013; Pore et al. 2016), suggesting its involvement in TLR4 activation. Deficiency of ezrin in LPS-stimulated B cells is associated with increased production of the immune regulatory cytokine IL-10 through NF-κB and interferon regulatory factor 3 (IRF-3) activation (Pore et al. 2016), suggesting a role for ezrin in regulating inflammation. Additionally, ezrin deactivation is involved in mediating the morphological changes and cytoskeletal restructuring required for chemotaxis of B cells (Parameswaran et al. 2011). Chemokine stimulation of B cells induces the concentration of ezrin at the lamellipodia (Parameswaran and Gupta 2013). A consitutively active mutant of ezrin does not localize to the lamellipodia and inhibits the migration of B cells, and B cells treated ex vivo with a serine/threonine phosphatase inhibitor fail to home to secondary lymphoid organs upon adoptive transfer (Parameswaran et al. 2011) demonstrating an important role for conformational switching of ezrin in B cell migration.
Ezrin, Fig. 2

Spatial regulation of lymphocyte activation by ezrin. Ezrin is constitutively phosphorylated in resting B and T cells. (a) After antigen binding to the BCR, ezrin is dephosphorylated and assumes an inactive confirmation, releasing surface molecules such as Cbp/PAG and the actin cytoskeleton. At the same time, the actin cytoskeleton undergoes depolymerization. Ezrin is then rephosphorylated and actin is repolymerized, stabilizing the BCR signalosome. (b) Upon interaction of the TCR with the MHC-peptide complex ezrin is rapidly dephosphorylated releasing both actin and membrane proteins such as CD43. TCRs and costimulatory molecules localize to the immunological synapse whereas CD43 is targeted to the distal pole

T Cell Immunity

Activation of T cells requires binding of the T cell receptor (TCR) to an antigen-MHC complex on an antigen presenting cell (APC). Similar to the BCR, antigen-induced clustering of TCRs is important for T cell activation. During T cell activation, the T cell and APC form an immunological synapse (IS), which brings together a variety of cognate signaling receptors required for full activation of T cells. The TCRs in resting T cells are stabilized by phosphorylated ezrin (Shaffer et al. 2009), and following its engagement by an antigen-MHC complex ezrin undergoes transient dephosphorylation of T567 and becomes inactive, relaxing the cytoskeleton and releasing the TCRs and other surface molecules from physical constraints (Fig. 2b) (Faure et al. 2004). The TCR and CD28 as well as adhesion and signaling proteins cluster in the IS, whereas CD43, a negative regulator of T cell activation, is sequestered to the uropod, which is localized distal to the immune synapse (Fig. 2b) (Allenspach et al. 2001; Martinelli et al. 2013). Expression of a dominant negative mutant of ezrin lacking the actin-binding domain is sufficient to block the concentration of CD43 in the uropod, decreasing IL-2 and IFN-γ production in activated T cells (Allenspach et al. 2001), demonstrating the role of ERM proteins in organization of the T cell surface receptors for efficient T cell activation. Additionally, ezrin has also been found to play a role in recruitment of the tyrosine kinase ZAP-70 to the IS during activation of the TCR (Fig. 2b) (Ilani et al. 2007). Following immune response and resolution, ezrin may also play a role in maintaining the sensitivity of antigen-exposed T cells by stabilizing enrichment of TCR complexes in clusters (Kumar et al. 2011; Sherman et al. 2011).

Other Immune Cells

During inflammatory responses, endothelial cells can express a variety of adhesion molecules capable of binding blood neutrophils. Surface molecules on the neutrophils act as ligands for these adhesion molecules, leading to sticking and rolling of neutrophils on the endothelial wall, where they are trapped and ultimately undergo transendothelial extravasation (Butcher 1991; Diacovo et al. 1996). This process is mediated by the expression of E-, P-, and L-selectins (Kansas 1996). P-selectin glycoprotein ligand 1 (PSGL-1) is expressed by neutrophils, binds to all three selectins, and interacts with ezrin as well as another member of the ERM family, moesin, in myeloid lineage cells (Alonso-Lebrero et al. 2000; Snapp et al. 2002). Activation of neutrophils by chemokines such as IL-8 and C5a leads to polarization of PSGL-1 leading to increased binding to selectins (Alonso-Lebrero et al. 2000; Rossy et al. 2009). In addition to sticking and rolling, PSGL-1-engagement by selectins also induces the recruitment of spleen tyrosine kinase (Syk) into lipid rafts (Abbal et al. 2006) leading to signaling, an interaction mediated by ERM proteins (Urzainqui et al. 2002; Spertini et al. 2012). Further, ezrin and moesin have been shown to interact with leukocyte binding receptors such as vascular cell adhesion molecule-1 (VCAM-1) on the apical surface of endothelial cells, and aid in leukocyte transmigration (Heiska et al. 1998; Barreiro et al. 2002). Furthermore, in monocytes and dendritic cells, ezrin is involved in the formation and maturation of the phagosome (Erwig et al. 2006).

Role in Cancer Pathogenesis

Ezrin is physiologically expressed in normal human tissues of both epithelial and mesenchymal origin. However, its expression has also been demonstrated in several human cancer cell lines as well as cancers of different cellular origins using tissue microarrays and immunohistochemistry. The expression of ezrin was found to be increased in cancerous tissue compared to corresponding normal tissues, with cancers of mesenchymal origin expressing greater levels than those of epithelial origin. Cancers associated with increased ezrin expression include breast cancer, lung cancer, prostate cancer, gastric cancer, esophageal squamous cell cancers, colorectal cancer, pancreatic adenocarcinoma, ovarian cancer, melanoma, glioblastoma, and astrocytic brain tumors (Fig. 3). Ezrin was also identified a marker of metastasis with higher expression seen in metastatic osteosarcoma and rhabdomyosarcoma. Higher level of ezrin expression has been clinically correlated with poor prognosis − reduced disease-free survival and overall survival. Due to its crucial role in membrane-cytoskeletal linkage, ezrin influences multiple components of metastasis including cell survival, motility, adherence, and invasion. Several signaling pathways have been implicated in bringing about the effects of ezrin on cellular survival, proliferation, and metastasis.
Ezrin, Fig. 3

Regulation of cancer cell signaling by ezrin. Ezrin expression and/or phosphorylation is increased in several human cancers and promotes cell survival and metastasis through the activation of a variety of signaling processes and pathways

Cell Survival

Ezrin mediates cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways. The phosphorylated Tyrosine-353 residue of ezrin binds to the carboxyl terminal SH2 domain of the p85 regulatory subunit of PI3K (Gautreau et al. 1999). In mouse models of metastatic osteosarcoma, reduction in ezrin levels is associated with reduced MAPK and Akt activity (Fig. 3) (Khanna et al. 2004; Ren and Khanna 2014). Ezrin also provides positive feedback to myc oncogene in prostate cancer, through the PI3K/Akt pathway. The myc oncogene, in turn, under the influence of testosterone, stimulates the transcription of ezrin by binding to the proximal promoter region of ezrin (Chuan et al. 2010). Interference with ezrin’s activity by expression of a dominant negative mutant, knockdown of expression, or treatment with a small molecular inhibitor reduces the growth of diffuse large B cell lymphoma cell lines in vitro and xenografts growth in vivo (Pore et al. 2015).

Cell Motility, Adherence, and Invasion

Physiologically, ezrin plays an important role in maintaining the structure of cellular microvilli such as in intestinal epithelial cells and lymphoid cells. Ezrin mediates cell protrusion and enables cancer cells to metastasize from their primary location to distant sites. Decreased expression of ezrin has been shown to reduce cell proliferation, migration, and invasion both in vitro and in vivo. The signaling processes and pathways regulated by ezrin in breast cancer, osteosarcoma, rhabdomyosarcoma, lung cancer, melanoma, and gastrointestinal cancer metastasis (Li et al. 2011; Clucas and Valderrama 2015; Ghaffari et al. 2014; Celik et al. 2016; Yu et al. 2004; Pujuguet et al. 2003; Srivastava et al. 2005; Bruce et al. 2007; Lam et al. 2011) are illustrated in Fig. 3.

Summary

Ezrin is a ubiquitously expressed protein with multiple sites for protein-protein interaction and exerts context-specific regulation in a large variety of cells. Its normal functions in cell signaling, adhesion, migration, proliferation, and survival are often coopted in cancer, autoimmunity, and inflammation, making it an appealing therapeutic target in the future.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Neetu Gupta
    • 1
  • Mala Upadhyay
    • 2
  • Michael Cheung
    • 2
  • Nabanita Bhunia
    • 2
  1. 1.Department of Immunology, Lerner Research InstituteCleveland Clinic FoundationClevelandUSA
  2. 2.Department of ImmunologyCleveland Clinic FoundationClevelandUSA