Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


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


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.


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.


  1. Abbal C, Lambelet M, Bertaggia D, Gerbex C, Martinez M, Arcaro A, et al. Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions. Blood. 2006;108(10):3352–9.PubMedCrossRefGoogle Scholar
  2. Allenspach EJ, Cullinan P, Tong J, Tang Q, Tesciuba AG, Cannon JL, et al. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity. 2001;15(5):739–50.PubMedCrossRefGoogle Scholar
  3. Alonso-Lebrero JL, Serrador JM, Dominguez-Jimenez C, Barreiro O, Luque A, del Pozo MA, et al. Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with moesin and ezrin in myeloid cells. Blood. 2000;95(7):2413–9.PubMedGoogle Scholar
  4. Amieva MR, Wilgenbus KK, Furthmayr H. Radixin is a component of hepatocyte microvilli in situ. Exp Cell Res. 1994;210(1):140–4.PubMedCrossRefGoogle Scholar
  5. Barreiro O, Yáñez-Mó M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, et al. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol. 2002;157(7):1233–45.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Belkina NV, Liu Y, Hao JJ, Karasuyama H, Shaw S. LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation. Proc Natl Acad Sci USA. 2009;106(12):4707–12.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Berryman M, Franck Z, Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci. 1993;105(Pt 4):1025–43.PubMedGoogle Scholar
  8. Berryman M, Gary R, Bretscher A. Ezrin oligomers are major cytoskeletal components of placental microvilli: a proposal for their involvement in cortical morphogenesis. J Cell Biol. 1995;131(5):1231–42.PubMedCrossRefGoogle Scholar
  9. Bretscher A. Purification of an 80,000-dalton protein that is a component of the isolated microvillus cytoskeleton, and its localization in nonmuscle cells. J Cell Biol. 1983;97(2):425–32.PubMedCrossRefGoogle Scholar
  10. Bretscher A, Gary R, Berryman M. Soluble ezrin purified from placenta exists as stable monomers and elongated dimers with masked C-terminal ezrin-radixin-moesin association domains. Biochemistry. 1995;34(51):16830–7.PubMedCrossRefGoogle Scholar
  11. Bruce B, Khanna G, Ren L, Landberg G, Jirstrom K, Powell C, et al. Expression of the cytoskeleton linker protein ezrin in human cancers. Clin Exp Metastasis. 2007;24(2):69–78.PubMedCrossRefGoogle Scholar
  12. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991;67(6):1033–6.PubMedCrossRefGoogle Scholar
  13. Celik H, Bulut G, Han J, Graham GT, Minas TZ, Conn EJ, et al. Ezrin inhibition up-regulates stress response gene expression. J Biol Chem. 2016;291(25):13257–70.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem Sci. 1998;23(8):281–2.PubMedCrossRefGoogle Scholar
  15. Chuan YC, Iglesias-Gato D, Fernandez-Perez L, Cedazo-Minguez A, Pang ST, Norstedt G, et al. Ezrin mediates c-Myc actions in prostate cancer cell invasion. Oncogene. 2010;29(10):1531–42.PubMedCrossRefGoogle Scholar
  16. Clucas J, Valderrama F. ERM proteins in cancer progression. J Cell Sci. 2015;128(6):1253.PubMedCrossRefGoogle Scholar
  17. Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH. Platelet-mediated lymphocyte delivery to high endothelial venules. Science. 1996;273(5272):252–5.PubMedCrossRefGoogle Scholar
  18. Dransfield DT, Bradford AJ, Smith J, Martin M, Roy C, Mangeat PH, et al. Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. EMBO J. 1997;16(1):35–43.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Erwig L-P, McPhilips KA, Wynes MW, Ivetic A, Ridley AJ, Henson PM. Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by Rho GTPases and ezrin–radixin–moesin (ERM) proteins. Proc Natl Acad Sci U S A. 2006;103(34):12825–30.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Faure S, Salazar-Fontana LI, Semichon M, Tybulewicz VL, Bismuth G, Trautmann A, et al. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat Immunol. 2004;5(3):272–9.PubMedCrossRefGoogle Scholar
  21. Funayama N, Nagafuchi A, Sato N, Tsukita S. Radixin is a novel member of the band 4.1 family. J Cell Biol. 1991;115(4):1039–48.PubMedCrossRefGoogle Scholar
  22. Gary R, Bretscher A. Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Mol Biol Cell. 1995;6(8):1061–75.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Gautreau A, Poullet P, Louvard D, Arpin M. Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96(13):7300–5.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Ghaffari A, Hoskin V, Szeto A, Hum M, Liaghati N, Nakatsu K, et al. A novel role for ezrin in breast cancer angio/lymphangiogenesis. Breast Cancer Res. 2014;16(5):438.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Gould KL, Bretscher A, Esch FS, Hunter T. cDNA cloning and sequencing of the protein-tyrosine kinase substrate, ezrin, reveals homology to band 4.1. EMBO J. 1989;8(13):4133–42.PubMedPubMedCentralGoogle Scholar
  26. Granes F, Urena JM, Rocamora N, Vilaro S. Ezrin links syndecan-2 to the cytoskeleton. J Cell Sci. 2000;113(Pt 7):1267–76.PubMedGoogle Scholar
  27. Gupta N, Wollscheid B, Watts JD, Scheer B, Aebersold R, DeFranco AL. Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulates antigen receptor-mediated lipid raft dynamics. Nat Immunol. 2006;7(6):625–33.PubMedCrossRefGoogle Scholar
  28. Heiska L, Alfthan K, Gronholm M, Vilja P, Vaheri A, Carpen O. Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. J Biol Chem. 1998;273(34):21893–900.PubMedCrossRefGoogle Scholar
  29. Helander TS, Carpen O, Turunen O, Kovanen PE, Vaheri A, Timonen T. ICAM-2 redistributed by ezrin as a target for killer cells. Nature. 1996;382(6588):265–8.PubMedCrossRefGoogle Scholar
  30. Hunter T, Cooper JA. Epidermal growth factor induces rapid tyrosine phosphorylation of proteins in A431 human tumor cells. Cell. 1981;24(3):741–52.PubMedCrossRefGoogle Scholar
  31. Ilani T, Khanna C, Zhou M, Veenstra TD, Bretscher A. Immune synapse formation requires ZAP-70 recruitment by ezrin and CD43 removal by moesin. J Cell Biol. 2007;179(4):733–46.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood. 1996;88(9):3259.PubMedGoogle Scholar
  33. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10(2):182–6.PubMedCrossRefGoogle Scholar
  34. Krieg J, Hunter T. Identification of the two major epidermal growth factor-induced tyrosine phosphorylation sites in the microvillar core protein ezrin. J Biol Chem. 1992;267(27):19258–65.PubMedGoogle Scholar
  35. Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT, Valpuesta JM, et al. Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes. Immunity. 2011;35(3):375–87.PubMedCrossRefGoogle Scholar
  36. Lam EK, Wang X, Shin VY, Zhang S, Morrison H, Sun J, et al. A microRNA contribution to aberrant Ras activation in gastric cancer. Am J Transl Res. 2011;3(2):209–18.PubMedPubMedCentralGoogle Scholar
  37. Li L, Wang YY, Zhao ZS, Ma J. Ezrin is associated with gastric cancer progression and prognosis. Pathol Oncol Res. 2011;17(4):909–15.PubMedCrossRefGoogle Scholar
  38. Martin M, Roy C, Montcourrier P, Sahuquet A, Mangeat P. Three determinants in ezrin are responsible for cell extension activity. Mol Biol Cell. 1997;8(8):1543–57.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Martinelli S, Chen EJ, Clarke F, Lyck R, Affentranger S, Burkhardt JK, et al. Ezrin/radixin/moesin proteins and flotillins cooperate to promote uropod formation in T cells. Front Immunol. 2013;4:84.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, et al. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol. 1998;140(3):647–57.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Nakamura N, Oshiro N, Fukata Y, Amano M, Fukata M, Kuroda S, et al. Phosphorylation of ERM proteins at filopodia induced by Cdc42. Genes Cells. 2000;5(7):571–81.PubMedCrossRefGoogle Scholar
  42. Oshiro N, Fukata Y, Kaibuchi K. Phosphorylation of moesin by rho-associated kinase (Rho-kinase) plays a crucial role in the formation of microvilli-like structures. J Biol Chem. 1998;273(52):34663–6.PubMedCrossRefGoogle Scholar
  43. Pakkanen R, Vaheri A. Cytovillin and other microvillar proteins of human choriocarcinoma cells. J Cell Biochem. 1989;41(1):1–12.PubMedCrossRefGoogle Scholar
  44. Pakkanen R, Hedman K, Turunen O, Wahlstrom T, Vaheri A. Microvillus-specific Mr 75,000 plasma membrane protein of human choriocarcinoma cells. J Histochem Cytochem. 1987;35(8):809–16.PubMedCrossRefGoogle Scholar
  45. Parameswaran N, Gupta N. Re-defining ERM function in lymphocyte activation and migration. Immunol Rev. 2013;256(1):63–79.PubMedCrossRefGoogle Scholar
  46. Parameswaran N, Matsui K, Gupta N. Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis. J Immunol. 2011;186(7):4088–97.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Parameswaran N, Enyindah-Asonye G, Bagheri N, Shah NB, Gupta N. Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine-phosphorylated ezrin. J Immunol. 2013;190(5):2017–26.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Pietromonaco SF, Simons PC, Altman A, Elias L. Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence. J Biol Chem. 1998;273(13):7594–603.PubMedCrossRefGoogle Scholar
  49. Pore D, Parameswaran N, Matsui K, Stone MB, Saotome I, McClatchey AI, et al. Ezrin tunes the magnitude of humoral immunity. J Immunol. 2013;191(8):4048–58.PubMedCrossRefGoogle Scholar
  50. Pore D, Bodo J, Danda A, Yan D, Phillips JG, Lindner D, et al. Identification of ezrin-radixin-moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma. Leukemia. 2015;29(9):1857–67.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Pore D, Matsui K, Parameswaran N, Gupta N. Cutting edge: ezrin regulates inflammation by limiting B cell IL-10 production. J Immunol. 2016;196(2):558–62.PubMedCrossRefGoogle Scholar
  52. Pujuguet P, Del Maestro L, Gautreau A, Louvard D, Arpin M. Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Mol Biol Cell. 2003;14(5):2181–91.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Reczek D, Berryman M, Bretscher A. Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol. 1997;139(1):169–79.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Ren L, Khanna C. Role of ezrin in osteosarcoma metastasis. Adv Exp Med Biol. 2014;804:181–201.PubMedCrossRefGoogle Scholar
  55. Rossy J, Schlicht D, Engelhardt B, Niggli V. Flotillins interact with psgl-1 in neutrophils and, upon stimulation, rapidly organize into membrane domains subsequently accumulating in the uropod. PLoS One. 2009;4(4):e5403.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Roy C, Martin M, Mangeat P. A dual involvement of the amino-terminal domain of ezrin in F- and G-actin binding. J Biol Chem. 1997;272(32):20088–95.PubMedCrossRefGoogle Scholar
  57. Shaffer MH, Dupree RS, Zhu P, Saotome I, Schmidt RF, McClatchey AI, et al. Ezrin and moesin function together to promote T cell activation. J Immunol. 2009;182(2):1021–32.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Sherman E, Barr V, Manley S, Patterson G, Balagopalan L, Akpan I, et al. Functional nanoscale organization of signaling molecules downstream of the T cell antigen receptor. Immunity. 2011;35(5):705–20.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Snapp KR, Heitzig CE, Kansas GS. Attachment of the PSGL-1 cytoplasmic domain to the actin cytoskeleton is essential for leukocyte rolling on P-selectin. Blood. 2002;99(12):4494–502.PubMedCrossRefGoogle Scholar
  60. Spertini C, Baïsse B, Spertini O. Ezrin-radixin-moesin-binding sequence of psgl-1 glycoprotein regulates leukocyte rolling on selectins and activation of extracellular signal-regulated kinases. J Biol Chem. 2012;287(13):10693–702.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Srivastava J, Elliott BE, Louvard D, Arpin M. Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol Biol Cell. 2005;16(3):1481–90.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Suni J, Narvanen A, Wahlstrom T, Aho M, Pakkanen R, Vaheri A, et al. Human placental syncytiotrophoblastic Mr 75,000 polypeptide defined by antibodies to a synthetic peptide based on a cloned human endogenous retroviral DNA sequence. Proc Natl Acad Sci USA. 1984;81(19):6197–201.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S, et al. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem. 1997;272(37):23371–5.PubMedCrossRefGoogle Scholar
  64. Treanor B, Depoil D, Gonzalez-Granja A, Barral P, Weber M, Dushek O, et al. The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity. 2010;32(2):187–99.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Treanor B, Depoil D, Bruckbauer A, Batista FD. Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity. J Exp Med. 2011;208(5):1055–68.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Tsukita S, Oishi K, Sato N, Sagara J, Kawai A. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994;126(2):391–401.PubMedCrossRefGoogle Scholar
  67. Urzainqui A, Serrador JM, Viedma F, Yanez-Mo M, Rodriguez A, Corbi AL, et al. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity. 2002;17(4):401–12.PubMedCrossRefGoogle Scholar
  68. Yao X, Cheng L, Forte JG. Biochemical characterization of ezrin-actin interaction. J Biol Chem. 1996;271(12):7224–9.PubMedCrossRefGoogle Scholar
  69. Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10(2):175–81.PubMedCrossRefGoogle Scholar
  70. Zhou R, Cao X, Watson C, Miao Y, Guo Z, Forte JG, et al. Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation. J Biol Chem. 2003;278(37):35651–9.PubMedCrossRefGoogle Scholar

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