[Frontiers in Bioscience 11, 1987-1997, May 1, 2006]

Role of ERM (ezrin-radixin-moesin) proteins in T lymphocyte polarization, immune synapse formation and in T cell receptor-mediated signaling

Stephanie Charrin and Andres Alcover

Unite de Biologie Cellulaire des Lymphocytes, Institut Pasteur, 25, rue Dr Roux, 75724 Paris Cedex 15, France


1. Abstract
2. Introduction
3. The ERM family of proteins
3.1. Activation of ERM proteins
3.2. Involvement of ERM proteins in cell cortex organization
3.3. Involvement of ERM proteins in intracellular signaling
4. Involvement of ERM proteins in T lymphocyte physiology
4.1. Involvement of ERM proteins in T cell polarization during lymphocyte migration
4.2. Involvement of ERM proteins during the formation of the immunological synapse
4.3. Involvement of ERM proteins in T cell intracellular signaling
5. Conclusions and perspectives
6. Acknowledgements
7. References


Following antigen recognition, T lymphocytes undergo strong actin cytoskeletal rearrangements. These play a crucial role in the molecular reorganization at the contact site between the T lymphocyte and the antigen presenting cell, termed the immunological synapse. Moreover, they are necessary for T cell activation that leads to cytokine secretion, T cell proliferation and effector function. Little is known on how membrane and signaling molecules interact with the actin cytoskeleton during these processes. Here we review the function of the ERM family of membrane-microfilament linkers, making emphasis on the role of these proteins in T lymphocyte physiology. We discuss how ERM proteins are involved in membrane reorganization during T lymphocyte polarization and immune synapse formation, and how these proteins may contribute to T cell receptor-mediated intracellular signaling that leads to T cell activation.


Antigen recognition and subsequent T cell activation require the appropriate interaction between T cells and antigen presenting cells (APC). This interaction involves a series of events that depend on membrane and actin cytoskeleton dynamics, such as cell motility, cell-cell adhesion, and molecular relocalization that leads to cell polarization. Initial T cell receptor (TCR) signaling induces actin cytoskeleton rearrangements, which in turn are necessary for the stability of T cell-APC interactions, the organization of the contact zone between T cell and the APC, termed the immunological synapse, and for T cell activation. The immunological synapse appears as a complex molecular reorganization at the contact site between T cells and APCs. There, T cell receptors (TCR), co-receptors, adhesion molecules, as well as intracellular signaling and cytoskeleton components concentrate and eventually segregate into distinct supramolecular clusters that redistribute following a precise relative topology. Immune synapse formation requires a functional actin and myosin cytoskeleton and agonistic TCR stimulation (reviewed in (1-4)).

Depending on the type and state of maturation of the T cell, the type and state of activation of the APC, and the stimulatory capacity of the antigen, the extent and dynamics of T cell-APC interactions, as well as the physical organization of immune synapses may be different. Thus, the molecular patterning forming central and peripheral supra-molecular activation clusters (5, 6) may not be always observed. However, common features appear clear, such as the spatial and temporal concentration of a variety of receptors, cytoskeletal and signaling proteins in the area of cell-cell contact. Immunological synapses are thought to serve to structure in time and space the complex communication between the T lymphocyte and the APC, in a way to ensure efficient antigen recognition and controlled T cell activation, and to provide stimuli to the APC (reviewed in (7, 8)).

The role of the actin cytoskeleton in T cell-APC interactions and subsequent T cell activation has been the object of active investigation during the last decade. An important question in the field is how interactions between the plasma membrane and the actin cytoskeleton take place and control the formation of the immunological synapse, as well as T cell activation. Various actin cytoskeleton-associated proteins were found to be involved. Talin was the first to be described as being recruited to the T cell-APC contact (9), and to localize in the peripheral zone of the immunological synapse (5). Talin can interact with integrins and with the actin cytoskeleton and may be involved in the stabilization of adhesion between the T cell and the APC (10). Moreover, the adaptor protein CD2AP links CD2 signals to the actin cytoskeleton via WASP (Wiscott-Aldrich Syndrome Protein) (11, 12). However, the role of CD2AP appears more complex, being also involved in TCR downregulation at the synapse (13). Recently, several laboratories including ours turned their attention to the ERM (ezrin-radixin-moesin) family of membrane-cytoskeleton crosslinkers. The data cumulated during the last several years indicate that these proteins may be important regulators of T cell functions. We briefly review here the functions and the putative importance of these proteins in T lymphocytes and other cell types, and we focus our discussion on aspects concerning T cell polarization, immune synapse formation and T cell activation.

3. The ERM family of proteins

Ezrin, radixin and moesin are highly homologous proteins that link membrane components with the actin cytoskeleton. They were originally characterized as structural components of the cell cortex. They form, together with merlin/schwannomin, the ERM family of proteins (reviewed in (14-16)). Ezrin radixin and moesin share a high degree (about 75%) of amino acid identity and are highly similar to the single forms of this protein expressed in Drosophila (Dmoesin) and Caenorhabditis elegans (ERM-1). The fourth member, merlin/schwannomin displays a lower degree of homology with the other members of the family (49% identity with ezrin) and appears to have distinct functions. Merlin is the product of the tumor suppressor gene mutated in the neurofibromatosis type 2 syndrome. ERM proteins belong to the erythrocyte protein 4.1 super-family that are characterized by a conserved ~300-residue globular N-terminal domain, the FERM domain (Four.1-Ezrin-Radixin-Moesin). The FERM domain is also found in a wide variety of proteins including the erythrocyte band 4.1 protein, talin, as well as several tyrosine kinases and phosphatases. The FERM domain is followed by an alpha-helical domain and a charged C-terminal region with a binding site to filamentous actin (F-actin) at its extremity. Ezrin, radixin and merlin also contain a polyproline region between the helical and C-terminal domains. The FERM domain interacts with membrane components and most signaling molecules, whereas the C-terminus binds with the actin cytoskeleton (Figure 1).

ERMs can mediate the anchoring of some transmembrane proteins to the actin cytoskeleton, either directly, or through adapter molecules, such as EBP50. They control cell shape, cytokinesis and cell adhesion in various cell types including lymphocytes. In addition, ERMs are involved in intracellular signaling. ERM proteins appear therefore as important molecular integrators in a variety of cell functions, and may be therefore involved in tumor development (14-16).

ERM proteins are widely expressed throughout the organism, being, at least two of them, co-expressed in numerous cell types. However, their relative expression varies among the different tissues, indicating some specific functions. For instance, ezrin is found primarily in the apical region of epithelial cells, whereas moesin is enriched in endothelial and hematopoietic cells. Ezrin and moesin were found co-expressed, and radixin absent, in human lymphocytes, monocytes and neutrophils. Moesin is predominant ERM protein in these cells and the only one detected in platelets. In contrast, in human natural killer cells all three ERMs were present. The specific function of ERM proteins co-expressed in a particular cell type is not well defined. In stimulated lymphocytes, ezrin was cleaved by calpain, whereas moesin was not, suggesting that these two ERM proteins may play distinct functions (17-20). Moreover, the study of mice deficient in individual ERM proteins reveal that these proteins may have overlapping functions in many tissues, since these mice do not have general alterations. Nevertheless, some of these deficient mice reveal very defined functions of these proteins in particular tissues (21-24).

3.1. Activation of ERM proteins

ERM proteins exist under two conformations: a "dormant" state, in which the proteins present a head to tail folded conformation, and an "active" state, in which the protein is unfolded and fully capable to interact with membrane components and with the actin cytoskeleton (Figure 2). The folded conformation is stabilized through the intramolecular interaction of the FERM domain with the 100 amino acid C-terminal end of the protein (25). This interaction masks membrane and F-actin-binding sites (26, 27). Intermolecular association of these two opposite ERM regions may also occur leading to ERM homo- or hetero-dimerization. This is important in cellular morphogenesis (28).

The activation of ERM proteins results in the unmasking of their membrane and cytoskeleton binding sites. This occurs through conformational changes induced by the binding of phosphoinisitides to the FERM domain and by the phosphorylation of a conserved threonine residue in the C-terminal domain (29-32). Protein kinase C (PKC)-theta and Rho-kinase were reported to phophorylate this threonine residue. However, the particular serine/threonine kinase that phosphorylates ERM proteins in vivo are poorly defined and may vary among different cells and with the type of stimulation (18, 30, 33, 34).

3.2. Involvement of ERM proteins in cell cortex organization

The role of ERM proteins in cell cortex organization has been extensively studied in epithelial cells. ERM proteins, and in particular ezrin, are enriched in the apical regions of polarized cells, where they play an important role in cell morphogenesis and in the localization of some transmembrane proteins in particular areas of the cell surface (14, 15).

The FERM domain can bind directly to the cytosolic tail of various transmembrane proteins (Table 1). They can also indirectly interact with other proteins via the adaptor protein EBP50. In T lymphocytes, the transmembrane proteins CD43, CD44, L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), intercellular adhesion molecules (ICAM-1, ICAM-2 and ICAM-3) and CD95 (APO-1/Fas), have been identified as ERM partners (Table 1). Although most transmembrane proteins appear to bind all three ERM proteins, the death receptor Fas/CD95 binds to ezrin, but not moesin, in T lymphocytes.

ERM proteins are involved in cell cortex organization at two important stages of T lymphocyte physiology: during the polarization and migration in response to chemokines, and during the formation of the immunological synapse upon antigen recognition (chapter 4).

3.3. Involvement of ERM in intracellular signaling

In addition to their capacity to interact with the cytoskeleton and with membrane components, ERM proteins were shown to interact with an increasing number of effectors of intracellular signaling (Table 1). Some interactions may be direct, while others are mediated by EBP50. ERM proteins are substrates of protein kinases that phosphorylate ERM proteins on tyrosine, or serine and threonine residues. These phosphorylation events are crucial for ERM function. Finally, the binding of phosphoinositides produced during the activation of phospholipid kinases, such as phosphatidylinositol-4,5-bisphosphate (PIP2) modulates ERM activity. Therefore, ERM proteins are themselves effectors of some intracellular signaling pathways (14, 15).

ERM proteins are important players in signaling pathways regulated by Rho-family GTPases. These pathways control cell morphogenesis, adhesion, motility and proliferation in response to a variety of cellular stimuli. Modulation of Rho family pathways may occur in part through interaction of ERM proteins with regulators or effectors of Rho family GTPases, such as RhoGDI, Dbl, Hamartin, Crk, Pak-1, N-WASP, etc. (34-43). Through interaction with the phosphatidylinositol-3 kinase (PI3K)/Akt pathway and with focal adhesion kinase, ezrin controls survival signals induced by adhesion molecules in epithelial cells (44, 45). Moreover, ezrin interaction with protein kinase C (PKC)-alpha modulates cell motility induced by this kinase (46). Ezrin interacts with c-Src, undergoes tyrosine phosphorylation, and cooperates with this kinase in deregulating cadherin-dependent cell-cell contacts in mammary carcinoma cells (47). This phenomenon is important for adhesion-mediated proliferation in epithelial cells (48). Interesting, phosphorylation of distinct tyrosine residues of ezrin appear to control the involvement of ezrin in different adhesion-dependent signaling pathways that lead to cell survival or proliferation (44, 48). ERM proteins could also participate in c-AMP-dependent protein kinase (PKA) pathways, since interaction between ERM and PKA, as well as ERM serine phosphorylation by PKA were reported. (49-53).


T lymphocytes are highly dynamic cells that migrate through the blood stream, the lymphoid tissues to ensure adaptive immune responses. To accomplish their

functions, T cells interact in various manners with a variety of cells in different tissues, such as endothelial cells in blood vessels or antigen presenting cells (dendritic cells, B cells and macrophages) in lymphoid organs. In addition, cytotoxic T lymphocytes interact with virus-infected target cells or tumor cells in order to eliminate them. The actin cytoskeleton plays a crucial role in all lymphocyte functions. ERM proteins, in particular, appear to perform key functions in cell polarity during lymphocyte migration and in T cell-APC interactions during the formation of the immunological synapse. The role of ERM proteins in intracellular T cell signaling starts to be elucidated, but it is still poorly explored.

4.1. Involvement of ERM proteins in polarization during T lymphocyte migration

ERM proteins play a crucial role in cell polarization during T lymphocyte migration. T cells polarize in response to adhesion or chemotactic stimuli displaying two poles: a lamellipodium-like structure at the front edge, which adheres to the extracellular substratum, and a posterior protrusion called the uropod. ERM proteins are involved in the generation of the uropod and in the anchoring of various transmembrane proteins (ICAMs, CD43, CD44, PSGL-1 and the death receptor CD95/Fas) to that area of the cell (54-60). The integrin LFA-1 is also concentrated in the uropod, although in the low affinity state (61). The precise function of the uropod in T cell physiology remains to be elucidated. However, the localized anchoring of adhesion molecules and some observations under the microscope suggest that the uropod could be an adhesive protrusion involved in the recruitment of bystander lymphocytes to areas of lymphocyte migration and in other immune cell interactions. Moreover, it may also facilitate the triggering of apoptosis by the Fas receptor (60, 62-64).

How do ERM proteins contribute to uropod formation is not completely elucidated. The activation of ERM proteins enhances the size of the uropod indicating a role of these proteins in the generation of this structure (54). However, inhibitors of the Rho kinase ROCK inhibited uropod formation, without inhibiting ERM protein threonine phosphorylation, or the polarization of CD44 (54). This indicates that uropod formation depends on ROCK activity but is not the consequence of ERM activation by ROCK phosphorylation. It is worth noting that ERM activation through phosphorylation by the Rho kinase was previously reported (30). However, the threonine kinase that phosphorylates ERM in polarized T lymphocytes in vivo remains undetermined. PKC-theta could be a candidate although it has not been formally proven (33, 34, 54). ERM proteins may therefore be important for the maintenance of uropod integrity, perhaps through local activation of the Rho signaling pathway (36), but not for uropod generation.

The mechanism that drives ERM protein localization to the uropod is not known. In epithelial cells, ERM proteins concentrate in areas rich in F-actin (15, 65). This suggests that ERM positioning in these cells might be controlled, at least in part, by actin polymerization. In contrast, in migrating lymphocytes, ERM proteins strongly concentrate at the uropod, whereas F-actin is mainly concentrated at the opposite side, in the leading edge (63). This indicates that ERM subcellular localization is not necessarily driven by the localization of F-actin and may be differently regulated following the physiological needs of each cell type.

ERM protein activation is modulated during T cell polarization and cell migration. Thus, threonine phosphorylation of ezrin and moesin is rapidly down-modulated upon chemokine stimulation. This correlates with loss of microvilli and polarization of chemokine-activated T cells. Moreover, expression of an ERM T/D mutant, which mimics the phosphorylated active form of ezrin (66), retards the loss of microvilli and the polarization induced by chemokines (67). This indicates that ERM proteins need to be desactivated in order to facilitate T cell migration and polarization. This is likely an important mechanism to facilitate morphological changes during cell extravasation. Interestingly, ERM proteins are also recruited within endothelial cells, together with the adhesion proteins VCAM-1 and ICAM-1 at the sites of contact with leukocytes, forming a docking structure for leukocyte adhesion (68). Therefore, ERM proteins seem to be crucial for forming adhesive structures on both the migrating leukocyte and the endothelial cell (69).

What is the relationship between Rho family GTPases and ERM proteins during T cell polarity and cell migration ? Rho family GTPases are key regulators of cell polarity (70). Consistently, these GTPases regulate T cell polarization and uropod formation in T lymphocytes. Thus, over-expression of constitutive active mutants of these GTPases inhibited T cell polarization in cells displaying motile cell morphology. Conversely, dominant negative mutants induce a polarized phenotype in round shaped cells (71). Moreover, chemokines activate the guanine nucleotide exchange factor for Rho GTPases Vav, and over-expression of dominant negative mutant of Vav inhibit lymphocyte polarization (72). ERM dephosphorylation, loss of microvilli and polarization in chemokine-activated T lymphocytes involves Rac1, rather than Rac2, Rho, or Cdc42, as assessed using inhibitory peptides and dominant negative mutants. Interestingly, constitutive active mutants of Rac1 and Cdc42 induced ERM protein dephosphorylation and loss of microvilli, whereas constitutive active Rho has the opposite effect, increased ERM phosphorylation and the size of microvilli (73). Therefore, ERM proteins seem to cross-talk with Rho-family GTPases in T cells and control lymphocyte morphological changes in response to chemokines.

4.2. Involvement of ERM proteins during the formation of the immunological synapse

T cells recognize antigens as molecular fragments displayed at the surface of APCs. To this end, lymphocytes screen the surface of numerous APCs in lymphoid organs. Transient interactions occur at this stage needing dynamic morphological changes. ERM proteins and their associated transmembrane proteins seem to play important roles during the different stages of T cell-APC interactions.

The ERM-associated adhesion molecule ICAM-3 on the surface of T cells plays a key role in establishing the initial interactions between the T lymphocyte and the APC. Thus, relocalization of this adhesion molecule to the sites of contact rapidly occurs, even in the absence of antigenic signal. Upon antigen recognition and stabilization of the T cell-APC interaction, ICAM-3 is mainly observed at the peripheral zone of the synapse. Interestingly, another ERM-binding protein, PSGL-1, which co-localizes with ICAM-3 in the uropod of migrating cells (57), relocalizes to the pole of the cell opposite to the immune synapse, only in antigen-stimulated cells (74). Although it is tempting to speculate that ERM binding to ICAM-3 and to PSGL-1 might be responsible for their respective subcellular translocation, it is at present unknown how ERM-interactions could mediate the translocation of these two proteins to opposite poles of the T cell. Perhaps, dynamic interaction between ICAM-3 and PSGL-1 with ERM proteins, as well as with other partners, might account for their specific relocalization during T cell-APC interactions.

In human T cells, we observed that ezrin and moesin concentrate in the F-actin rich membrane protrusions that establish the contact with the APC. Ezrin is first observed at the peripheral area of the immune synapse, covering, at later times, also the center of the T cell-APC contact (75-77). In mouse T cells, however, the accumulations of ERM proteins at the T cell-APC contact site appear difficult to observe. Ezrin and moesin were reported to be excluded from the T cell-APC contact site with no accumulation in the contact zone, or even found accumulated in the antipodal region of the APC contact site (78, 79).

Ezrin and moesin appear to be important to move their partner surface molecules CD43 out of the center of the immunological synapse (78, 79). CD43 is an abundant highly glycosylated and sialylated surface protein. Studies of CD43-deficient mice lead to propose that CD43 plays a negative regulatory role in T cell activation (80). It was therefore proposed that the large size of the CD43 extracellular domain (81) was impeding, by steric hindrance and negative charge, the effective interactions of other surface receptors. Consistent with this idea, CD43 was shown to be excluded from the T cell-APC contact site (82). CD43 exclusion was active and dependent on CD43 interaction with ERM proteins and the actin cytoskeleton. Thus, over-expression of CD43 mutated in the ERM binding stretch, or the FERM domain of ezrin, inhibited CD43 exclusion from the immune synapse and further T cell activation (78, 79). Additional work showed, however, that the steric barrier model of CD43 was not completely correct and that the presence of CD43 extracellular domain in the T cell-APC contact site may not be inhibitory. In contrast, the intracellular region of CD43 may negatively regulate T cell activation (83, 84). An apparent paradox to the CD43 inhibitory role is the observation that CD43 may also display co-stimulatory properties when cross-linked alone or together with the TCR by means of antibodies (85). However, since CD43 does not have an identified ligand on the APC, the co-stimulatory role of CD43 remains questionable.

Antigenic stimulation induces the rapid dephosphorylation of ezrin and moesin on the C-terminal threonine residue that controls ERM activation (79, 86). ERM dephosphorylation is controlled by Vav1 and Rac1. Interestingly, both Rac1 and Cdc42 constitutive active mutants induced ERM dephosphorylation, whereas the Rho active mutant had the opposite effect. However, only the Rac1 dominant negative mutant inhibited ERM dephosphorylation induced by TCR engagement. ERM inactivation appears to modulate cellular rigidity and facilitate T cell-APC conjugation (86). ERM proteins also influence molecular clustering at the synapse. Thus, perturbing ERM function by over-expression of the FERM domain has an inhibitory effect on TCR clustering (75). Moreover, ERM proteins through their associated adaptor EBP50 interact with Cbp-PAG, a Csk-associated signaling adaptor localized in membrane rafts. Through this interaction, ERM proteins link raft components with the actin cytoskeleton, modulating the dynamics of membrane rafts in T cells and the formation of the immune synapse. T cell activation downregulates Cbp-EBP-moesin interaction, indicating that this complexes may play a negative regulatory role in raft dynamics (87).

4.3. Involvement of ERM proteins in intracellular signaling in T lymphocytes

Although much less explored than in epithelial cells, ERM proteins were also shown to be involved in signaling pathways in leukocytes. Thus, ERM proteins appear involved in signaling triggered by the death receptor CD95, or those triggered by the adhesion proteins PSGL-1 or ICAM-1. Very little is known, however, whether ERM proteins are involved in antigen-triggered signal transduction.

The interaction of ezrin with CD95 (APO/Fas) is important for triggering the intracellular signaling cascade leading to apoptosis induced by this receptor. Interestingly, contrary to other receptors that can interact with several ERM proteins, Fas specifically interacts with ezrin on a region of the FERM domain. CD95 is polarized in the uropod of migrating lymphocytes. Moreover, CD95-mediated apoptosis requires the integrity of the actin cytoskeleton. Therefore, the interaction of CD95 with ezrin and its polarization appear to be key events for rendering human T lymphocytes sensitive to CD95-mediated apoptosis (60, 88).

Lymphocyte adhesion may also induce activation signals through ERM proteins. Thus, ezrin and moesin mediate signal transduction of PSGL-1, a leukocyte adhesion molecule involved in tethering and rolling on endothelium. ERM proteins interact with PSGL-1 and with the protein tyrosine kinase Syk via the ITAM (immuno-receptor tyrosine-based activation motif)-based motif contained in the FERM domain (89). In this way ezrin and moesin can mediate PSGL-1-induced Syk activation that leads to transcriptional activation. Moreover, ezrin appears to be involved in an ICAM-2-mediated cell survival signaling pathway (90). This pathway involves Src kinases, ROCK, PI3K and AKT (90) and is reminiscent of that described in epithelial cells (44).

Ezrin and moesin interact via EBP50 with the signaling adaptor Cbp/PAG (87). This protein is mainly localized in membrane rafts, and binds and modulates the activity of Csk, a protein tyrosine kinase that negatively regulates Src-family kinases (91). Although not formally proven, it is tempting to speculate that ERM proteins could, through their interaction with this adaptor, be involved in the regulation of the activity of Src family kinases in T cells.

Ezrin was shown to be a substrate of tyrosine kinases activated by TCR and CD4 stimulation (92, 93). Lck appears responsible for this phosphorylation (94). The importance of phosphorylated tyrosine residues in ezrin and moesin was previously shown in epithelial cells (44, 48), or in T cells activated by PSGL-1 (89). However, it remains unknown whether the TCR signaling cascade involves ERM proteins similarly to adhesion molecules.

Although the role of ERM proteins in antigen-triggered signaling cascades is unknown, it is tempting to speculate that ERM proteins could play a role in the spatio-temporal positioning of key signaling molecules that polarize upon TCR engagement. For instance, we have shown that in response to antigenic stimulation human T cells form transient membrane protrusions that partially engulf the APC and occupy the peripheral area of the immune synapse. These membrane protrusions are enriched in F-actin and ezrin (75, 76). Interestingly, we also observed that some key effectors of the TCR signaling cascade, such as Vav1 and Ly-GDI, or NEMO, also transiently accumulate in those cellular protrusions (95, 96). This suggests that these, and likely other signaling molecules, may interact with the actin cytoskeleton in those areas. ERM proteins might be candidates for these interactions. They could favor polarized interactions between signaling molecules in that pole of the cell (Figure 3 A). In addition, ERM could maintain signaling molecules anchored to the cytoskeleton, preventing their spontaneous interaction thereby buffering the intensity of the signaling cascade (Figure 3 B). Clearly, the role of ERM proteins in T cell signaling is still largely unexplored and it will need deeper investigation in the near future.


ERM proteins appear as key organizers of the cell cortex during different stages of T cell physiology. In addition, their role in signal transduction just starts to be elucidated. These proteins will likely play unexpected roles in T lymphocytes, due to the dynamics and the multiplicity of processes at which membrane and cytoskeleton rearrangements are crucial in T cell physiology.


S. Charrin is supported by a fellowship from La Ligue Contre le Cancer. The support of La Ligue Contre le Cancer (Comite de Paris), the Association pour la Recherche sur le Cancer (ARC), the Centre National pour la Recherche Scientifique (CNRS) and the Institut Pasteur is thankfully acknowledged. We thank M. I. Thoulouze for critical reading of the manuscript.


1. Sechi A. S. & J. Wehland: Interplay between TCR signalling and actin cytoskeleton dynamics. Trends Immunol. 25, 257-265 (2004)

2. Dustin M. L. & J. A. Cooper: The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nat. Immunol. 1, 23-29 (2000)

3. van den Merwe P. A.: Formation and function of the immunological synapse. Curr. Op. Immunol. 14, 293-298 (2002)

4. Krogsgaard M., J. B. Huppa, M. A. Purbhoo & M. M. Davis: Linking molecular events in T-cell activation and synapse formation. Semin. Immunol. 15, 307-315 (2003)

5. Monks C. R. F., B. A. Freiberg, H. Kupfer, N. Sciaky & A. Kupfer: Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82-86 (1998)

6. Grakoui A., S. K. Bromley, C. Sumen, M. M. Davis, A. S. Shaw, P. M. Allen & M. L. Dustin: The immunological synapse: a molecular machine controling T cell activation. Science 285, 221-227 (1999)

7. Trautmann A. & S. Valitutti: The diversity of immunological synapses. Curr. Op. Immunol. 15, 249-254 (2003)

8. Friedl P., A. T. den Boer & M. Gunzer: Tuning immune responses: diversity and adaptation of the immunological synapse. Nat. Revs. Immunol. 5, 532-545 (2005)

9. Kupfer A. & S. J. Singer: Cell biology of cytotoxic and helper T-cell functions : Immunofluorescence microscopic studies of single cells and cell couples. Annu. Rev. Immunol. 7, 309-337 (1989)

10. Critchley D. R.: Focal adhesions-the cytoskeletal connection. Curr. Op. Cell Biol. 12, 133-139 (2000)

11. Dustin M. L., M. W. Olszowy, A. D. Holdorf, J. Li, S. Bromley, N. Desai, P. Widder, F. Rosenberg, P. A. van den Merwe, P. Allen & A. S. Shaw: A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T cell contacts. Cell 94, 667-677 (1998)

12. Badour K., J. Zhang, F. Shi, M. K. H. McGavin, V. Rmapersad, L. A. Hardy, D. Field & K. A. Siminovitch: The Wiscott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18, 141-154 (2003)

13. Lee K. H., A. R. Dinner, C. Tu, G. Campi, S. Raychaudhuri, R. Varma, T. N. Sims, W. R. Burack, H. Wu, J. Wang, O. Kanagawa, M. Markiewicz, P. M. Allen, M. L. Dustin, A. K. Chakraborty & A. S. Shaw: The Immunological Synapse Balances T Cell Receptor Signaling and Degradation. Science 302, 1218-1222 (2003)

14. Bretscher A., K. Edwards & R. G. Fehon: ERM proteins and merlin: integrators at the cell cortex. Nat. Rev. Molec. Cell Biol. 3, 586-598 (2002)

15. Gautreau A., D. Louvard & M. Arpin: ERM proteins and NF2 tumor suppressor: the yin and yang of cortical actin organization and cell growth signaling. Curr. Op. Cell Biol. 14, 104-109 (2002)

16. McClatchey A. I.: Merlin and ERM proteins: unappreciated roles in cancer development ? Nat. Rev. Cancer 3, 877-883 (2003)

17. Berryman M., Z. Franck & A. Bretscher: Ezrin is concentrated in the apical microvilli of a wide variety od epithelial cells whereas moesin is found primarily in endothelial cells. J. Cell. Sci. 105, 1025-1042 (1993)

18. Nakamura F., M. R. Amieva & H. Furthmayr: Phosphorylation of threonine 558 in the carboxyl-terminal actin-binding domain of moesin by thrombin activation of human platelets. J. Biol. Chem. 270, 31377-31385 (1995)

19. Shcherbina A., A. Bretscher, D. M. Kenney & E. Remold-O'Donnell: Moesin, the major ERM protein of lymphocytes and platelets, differs from ezrin in its insensitivity to calpain. FEBS Lett. 443, 31-36 (1999)

20. Schwartz-Albiez R., A. Merling, H. Spring, P. Moller & K. Koretz: Differential expression of the microspike-associated protein moesin in human tissues. Eur. J. Cell Biol. 67, 189-198 (1995)

21. Doi Y., M. Itoh, S. Yonemura, S. Ishihara, H. Takano, T. Noda & S. Tsukita: Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout. J. Biol. Chem. 274, 2315-2321 (1999)

22. Saotome I., M. Curto & A. I. McClatchey: Ezrin Is Essential for Epithelial Organization and Villus Morphogenesis in the Developing Intestine. Dev. Cell 6, 855-864 (2004)

23. Kitajiri S., K. Fukumoto, M. Hata, H. Sasaki, T. Katsuno, T. Nakagawa, J. Ito, S. Tsukita & S. Tsukita: Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. J. Cell. Biol. 166, 559-570 (2004)

24. Kikuchi S., M. Hata, K. Fukumoto, Y. Yamane, T. Matsui, A. Tamura, S. Yonemura, H. Yamagishi, D. Keppler, S. Tsukita & S. Tsukita: Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat. Genet. 31, 320-325 (2002)

25. Pearson M. A., D. Recezk, A. Bretscher & P. A. Karplus: Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101, 259-270 (2000)

26. Gary R. & A. Bretscher: 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 6, 1061-1075 (1995)

27. Magendantz M., M. D. Henry, A. Lander & F. Solomon: Interdomain interactions of radixin in vitro. J. Biol. Chem. 270, 25324-25327 (1995)

28. Berryman M., D. Gary & A. Bretscher: Ezrin oligomers are major cytoskeletal components of placental microvilli: a proposal for their involvement in cortical morphogenesis. J. Cell Biol. 131, 1231-1242 (1995)

29. Barret C., C. Roy, P. Montcurrier, P. Mangeat & V. Niggli: Mutagenesis of the phosphatidylinositol 4,5-bisphosphate (PIP2) binding site in the NH2-terminal domain of ezrin correlates with its altered cellular distribution. J. Cell Biol. 151, 1067-1079 (2000)

30. Matsui T., M. Maeda, Y. Doi, S. Yonemura, M. Amano, K. Kaibuchi, S. Tsukita & S. Tsukita: Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head to tail association. J. Cell Biol. 3, 647-657 (1998)

31. Nakamura F., L. Huang, K. Pestonjamasp, E. J. Luna & H. Furthmayr: Regulation of F-actin binding to platelet moesin in vitro by both phosphorylation of threonine 558 and phosphatidylinositides. Mol. Biol. Cell 10, 2669-1685 (1999)

32. Fievet B. T., A. Gautreau, C. Roy, L. Del Maestro, P. Mangeat, D. Louvard & M. Arpin: Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J. Cell Biol. 164, 653-659 (2004)

33. Pietromonaco S. F., P. C. Simons, A. Altman & L. Elias: Protein kinase C-q phosphorylation of moesin in the actin-binding sequence. J. Biol. Chem. 273, 7594-7603 (1998)

34. Matsui T., S. Yonemura, S. Tsukita & S. Tsukita: Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinases. Curr. Biol. 9, 1259-1262 (1999)

35. Takahashi K., T. Sasaki, A. Mammoto, I. Hotta, K. Takaishi, H. Imamura, K. Nakano, A. Kodama & Y. Takai: Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl. Oncogene 16, 3279-3284 (1998)

36. Takahashi K., T. Sasaki, A. Mammoto, K. Takaishi, T. Kameyama, S. Tsukita, S. Tsukita & Y. Takai: Direct interaction of the Rho dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J. Biol. Chem. 272, 23371-23375 (1997)

37. Mackay D. G. J., F. Esch, H. Furthmayr & A. Hall: Rho- and Rac-dependent assembly of focal adhesion complexes and actin filaments in permeabilized fibroblasts: an essential role for ezrin/redixin/moesin proteins. J. Cell Biol. 138, 927-938 (1997)

38. Tran Quang C., A. Gautreau, M. Arpin & R. Treisman: Ezrin function is required for ROCK-mediated fibroblast transformation by the Net and Dbl oncogenes. EMBO J. 19, 4565-4576 (2000)

39. Lamb R. F., C. Roy, T. J. Diefenbach, H. V. Vinters, M. W. Johnson, D. G. Jay & A. Hall: The TSC1 tumor suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol. 2, 281-287 (2000)

40. Tsuda M., Y. Makino, T. Iwahara, H. Nishihara, H. Sawa, K. Nagashima, H. Hanafusa & S. Tanaka: Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid. J. Biol Chem. 279, 46843-46850 (2004)

41. Manchanda N., A. Lyubimova, H. Y. Ho, M. F. James, J. F. Gusella, N. Ramesh, S. B. Snapper & V. Ramesh: The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. J. Biol. Chem. 280, 12517-12522 (2005)

42. Pujuguet P., L. Del Maestro, A. Gautreau, D. Louvard & M. Arpin: Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Molec. Biol. Cell 14, 2181-2191 (2003)

43. Kissil J. L., E. W. Wilker, K. C. Johnson, M. S. Eckman & M. B. Yaffe: Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p-21 activated kinase, Pak1. Molec. Cell 12, 841-849 (2003)

44. Gautreau A., P. Poullet, D. Louvard & M. Arpin: Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. USA 96, 7300-7305 (1999)

45. Poullet P., A. Gautreau, G. Kadare, J. A. Girault, D. Louvard & M. Arpin: Ezrin interacts with focal adhesion kinase and induces its activation independently of cell-matrix adhesion. J. Biol. Chem. 276, 37686-37691 (2001)

46. Ng T., M. Parsons, W. E. Hughes, J. Monypenny, D. Zich, A. Gautreau, M. Arpin, Gschmeissner, P. J. Verveer, P. I. H. Bastiens & P. J. Parker: Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility. EMBO J. 20, 2723-2741 (2001)

47. Elliott B. E., H. Qiao, D. Louvard & M. Arpin: Co-operative effect of c-Src and ezrin in deregulation of cell-cell contacts and scattering of mammary carcinoma cells. J. Cell. Biochem. 92, 16-28 (2004)

48. Srivastava J., B. E. Elliott, D. Louvard & M. Arpin: Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol. Biol. Cell 16, 1481-1490 (2005)

49. Dransfield D. T., A. J. Bradford, J. Smith, M. Martin, C. Roy, P. H. Mangeat & J. R. Goldenring: Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. EMBO J. 16, 35-43 (1997)

50. Jeon S., S. Kim, E. Kim, J. E. Lee, S. J. Kim, Y. S. Juhnn, Y. S. Kim, C. D. Bae & J. Park: Chloride conductance is required for the protein kinase A and Rac1-dependent phosphorylation of moesin at Thr-558 by KCl in PC12 cells. J. Biol. Chem. 280, 12181-12189 (2005)

51. Alfthan K., L. Heiska, M. Gronholm, G. H. Renkema & O. Carpen: Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization. J. Biol. Chem. 279, 18559-18566 (2004)

52. Zhou R., X. Cao, C. Watson, Y. Miao, Z. Guo, J. G. Forte & X. Yao: Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation. J. Biol. Chem. 278, 35651-35659 (2003)

53. Grönholm M., L. Vossebein, C. R. Carlson, J. Kuja-Panula, T. Teesalu, K. Alfthan, A. Vaheri, H. Rauvala, F. W. Herberg & K. C. O. Tasken: Merlin links to the cAMP neuronal signaling pathway by anchoring the RI beta subunit of protein kinase A. J. Biol. Chem. 278, 41167-41172 (2003)

54. Lee J. H., T. Katakai, T. Hara, H. Gonda, M. Sugai & A. Shimizu: Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J. Cell Biol. 167, 327-337 (2004)

55. Serrador J. M., J. L. Alonso-Lebrero, M. A. del Pozo, H. Furthmayr, R. Schwartz-Albiez, J. Calvo, F. Lozano & F. Sánchez-Madrid: Moesin interacts with the cytoplasmic region of intercellular adhesion molecule-3 and is redistributed to the uropod of T lymphocytes during cell polarization. J. Cell Biol. 138, 1409-1423 (1997)

56. Serrador J. M., M. Nieto, J. L. Alonso-Lebrero, M. A. del Pozo, J. Calvo, H. Furthmayr, R. Schwartz-Albiez, F. Lozano, R. González-Amaro, P. Sánchez-Mateos & F. Sánchez-Madrid: CD43 interacts with moesin and ezrin and regulates its distribution to the uropods of T lymphocytes at the cell-cell contacts. Blood 91, 4632-4644 (1998)

57. Alonso-Lebrero J. L., J. M. Serrador, C. Dominguez-Jimenez, O. Barreiro, A. Luque, M. A. del Pozo, K. Snapp, G. Kansas, R. Schwartz-Albiez, H. Furthmayr, F. Lozano & F. Sanchez-Madrid: Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with moesin and ezrin in lymphoid cells. Blood 95, 2413-2419 (2000)

58. Serrador J. M., A. Urzainqui, J. L. Alonso-Lebrero, J. R. Cabrero, M. C. Montoya, M. Vicente-Manzanares, M. Yanez-Mo & F. Sanchez-Madrid: A juxta-membrane amino acid sequence of P-selectin glycoprotein ligand-1 is involved in moesin binding and ezrin/radixin/moesin-directed targeting at the trailing edge of migrating lymphocytes. Eur. J. Immunol. 32, 1560-1566 (2003)

59. Serrador J. M., M. Vicente-Manzanares, J. Calvo, O. Barreiro, M. C. Montoya, R. Schwartz-Albiez, H. Furthmayr, F. Lozano & F. Sanchez-Madrid: A novel serine-rich motif in the intercellular adhesion molecule 3 is critical for its ezrin/radixin/moesin-directed subcellular targeting. J. Biol. Chem. 277, 10400-10409 (2002)

60. Parlato S., A. M. Giammarioli, M. Logozzi, F. Lozupone, P. Matarrese, F. Luciani, M. Falchi, W. Malorni & S. Fais: CD95 (APO1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway. EMBO J. 19, 5123-5134 (2000)

61. Smith A., Y. R. Carrasco, P. Stanley, N. Kieffer, F. D. Batista & N. Hogg: A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes. J Cell Biol 170, 141-151 (2005)

62. del Pozo M. A., C. Cabañas, M. C. Montoya, A. Ager, P. Sánchez-Mateos & F. Sánchez-Madrid: ICAMs redistributed by chemokines to cellular uropods as a mechanism for recruitment of T lymphocytes. J. Cell Biol. 137, 493-508 (1997)

63. Sánchez-Madrid F. & M. A. del Pozo: Leukocyte polarization in cell migration and immune interactions. EMBO J. 18, 501-511 (1999)

64. Fais S. & W. Malorni: Leukocyte uropod formation and membrane/cytoskeleton linkage in immune interactions. J. Leukocyte Biol. 73, 556-563 (2003)

65. Bretscher A., D. Chambers, R. Nguyen & D. Reczek: ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Ann. Rev. Cell Dev. Biol. 16, 113-143 (2000)

66. Gautreau A., D. Louvard & M. Arpin: Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane. J. Cell Biol. 150, 193-203 (2000)

67. Brown M. J., R. Nijhara, J. A. Hallam, M. Gignac, K. M. Yamada, S. L. Erlandsen, J. Delon, M. Kruhlak & S. Shaw: Chemokine stimulation of human peripheral blood T lymphocytes induces rapid dephosphorylation of ERM proteins, which facilitates loss of microvilli and polarization. Blood 102, 3890-3899 (2003)

68. Barreiro O., M. Yanez-Mo, J. M. Serrador, M. C. Montoya, M. Vicente-Manzanares, R. Tejedor, H. Furthmayr & F. Sanchez-Madrid: Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J. Cell Biol. 157, 1233-1245 (2002)

69. Barreiro O., M. Vicente-Manzanares, A. Urzainki, M. Yanez-Mo & F. Sanchez-Madrid: Interactive protrusive structures during leukocyte adhesion and transendothelial migration. Front. Biosc. 9, 1849-1863 (2004)

70. Etienne-Manneville S.: Cdc42-the centre of polarity. J. Cell Sci. 117, 1291-1300 (2004)

71. del Pozo M. A., M. Vicente-Manzanares, R. Tejedor, J. M. Serrador & F. Sánchez-Madrid: Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609-3620 (1999)

72. Vicente-Manzanares M., A. Cruz-Adalia, N. B. Martin-Cofreces, J. R. Cabrero, M. Dosil, B. Alvarado-Sanchez, X. R. Bustelo & F. Sanchez-Madrid: Control of lymphocyte shape and the chemotactic response by the GTP exchange factor Vav. Blood 105, 3026-3034 (2005)

73. Nijhara R., P. B. van Hennik, M. L. Gignac, M. J. Kruhlak, P. L. Hordijk, J. Delon & S. Shaw: Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes. J. Immunol. 15, 4985-4993 (2004)

74. Montoya M. C., D. Sancho, G. Bonello, Y. Collette, C. Langlet, H. T. He, P. Aparicio, A. Alcover, D. Olive & F. Sanchez-Madrid: Role of ICAM-3 in the initial interaction of T lymphocytes and APCs. Nat. Immunol. 3, 159-168 (2002)

75. Roumier A., J. C. Olivo-Marin, M. Arpin, F. Michel, M. Martin, P. Mangeat, O. Acuto, A. Dautry-Varsat & A. Alcover: The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15, 715-728 (2001)

76. Das V., B. Nal, A. Roumier, V. Meas-Yedid, C. Zimmer, J. C. Olivo-Marin, P. Roux, P. Ferrier, A. Dautry-Varsat & A. Alcover: Membrane-cytoskeleton interactions during the formation of the immunological synapse and subsequent T cell activation. Immunol. Revs 189, 123-135 (2002)

77. Tomas E. M., T. A. Chau & J. Madrenas: Clustering of a lipid-raft associated pool of ERM proteins at the immunological synapse upon T cell receptor or CD28 ligation. Immunol. Lett. 83, 143-147 (2002)

78. Allenspach E. J., P. Cullinan, J. Tong, Q. Tang, A. G. Tesciuba, J. L. Cannon, S. M. Takahashi, R. Morgan, J. K. Burkhardt & A. I. Sperling: ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 15, 739-750 (2001)

79. Delon J., K. Kaibuchi & R. N. Germain: Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin. Immunity 15, 691-701 (2001)

80. Manjunath N., M. Correa, M. Ardman & B. Ardman: Negative regulation of T-cell adhesion and activation by CD43. Nature 377, 535-538 (1995)

81. Cyster J. G., D. M. Shotton & F. Williams: The dimensions of the T lymphocyte glycoprotein leukosialin and identification of linear proteins epitopes that can be modified by glycosylation. EMBO J. 10, 893 (1991)

82. Sperling A. I., J. R. Sedy, N. Manjunath, A. Kupfer, B. Ardam & J. K. Burkhardt: TCR signaling induces selective exclusion of CD43 from the T cell-antigen presenting cell contact site. J. Immunol. 161, 6459-6462 (1998)

83. Savage N. D. G., S. L. Kimzey, S. K. Bromley, K. G. Johnson, M. L. Dustin & J. M. Green: Polar redistribution of the sialoglycoprotein CD43: implications for T cell function. J. Immunol. 168, 3740-3746 (2002)

84. Tong J., E. J. Allespach, S. M. Takahashi, P. D. Mody, C. Park, J. K. Burkhardt & A. I. Sperling: CD43 regulation of T cell activation is not through steric inhibition of T cell-APC interactions but through an intracellular mechanism. J. Exp. Med. 199, 1277-1283 (2004)

85. Mattioli I., O. Dittrich-Breiholz, M. Livingstone, M. Kracht & M. L. Schmitz: Comparative analysis of T-cell costimulation and CD43 activation reveals novel signaling pathways and target genes. Blood 104, 3302-3304 (2004)

86. Faure S., L. I. Salazar-Fontana, M. Semichon, V. L. J. Tybulewicz, G. Bismuth, A. Trautmann, R. N. Germain & J. Delon: ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat. Immunol. 5, 272-279 (2004)

87. Itoh K., M. Sakakibara, S. Yamasaki, A. Takeuchi, H. Arase, M. Miyazaki, N. Nakajima, M. Okada & T. Saito: Negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly. J. Immunol. 168, 541-544 (2002)

88. Lozupone F., L. Lugini, P. Matarrese, F. Luciani, C. Federici, E. Iessi, P. Margutti, G. Stassi, W. Malorni & S. Fais: Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J. Biol. Chem. 279, 199-207 (2004)

89. Urzainki A., J. M. Serrador, F. Viedma, M. Yanez-Mo, A. Rodriguez, A. L. Corbi, J. L. Alonso-Lebrero, A. Luque, M. Deckert, J. Vazquez & F. Sanchez-Madrid: ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSLG-1. Immunity 17, 401-412 (2002)

90. Perez O. D., S. Kinoshita, Y. Hitoshi, D. G. Payan, T. Kitamura, G. P. Nolan & J. B. Lorens: Activation of the PKB/AKT pathway by ICAM-2. Immunity 16, 51-65 (2002)

91. Takeuchi S., Y. Takayama, A. Ogawa, K. Tamura & M. Okada: Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. J. Biol. Chem. 275, 29183-29186 (2000)

92. Egerton M., W. H. Burgess, D. Chen, B. J. Druker, A. Bretscher & L. E. Samelson: Identification of ezrin as an 81-kDa tyrosine-phosphorylated protein in T cells. J. Immunol. 149, 1847-1852 (1992)

93. Thuillier L., C. Hivroz, R. Fagard, C. Andreoli & P. Mangeat: Ligation of CD4 surface antigen induces rapid tyrosine phosphorylation of the cytoskeletal protein ezrin. Cell. Immunol. 156, 322-331 (1994)

94. Autero M., L. Heiska, L. Ronnstrand, A. Vaheri, C. G. Gahmberg & O. Carpen: Ezrin is a substrate for Lck in T cells. FEBS Lett. 535, 82-86 (2003)

95. Groysman M., I. Hornstein, A. Alcover & S. Katzav: Vav-1 and Ly-GDI, two regulators of Rho GTPases, function cooperatively as signal transducers in T cell antigen receptor-induced pathways. J. Biol. Chem. 277, 50121-50130 (2002)

96. Weil R., K. Schwanborn, A. Alcover, C. Bessia, V. Di Bartolo & A. Israël: Induction of the NF-kB cascade by recruitment of the scaffold molecule NEMO to the T cell receptor. Immunity 18, 13-26 (2003)

97. Yonemura S., M. Hirao, Y. Doi, N. Takahashi, T. Kondo, S. Tsukita & S. Tsukita: Ezrin/Radixin/Moesin (ERM) proteins bind to a positively charged aminoacid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43 and ICAM-2. J. Cell Biol. 140, 885-895 (1998)

98. Tsukita S., K. Oishi, N. Sato, J. Sagara, A. Kawai & S. Tsukita: ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J. Cell Biol. 126, 391-401 (1994)

99. Legg J. W. & C. M. Isacke: Identification and functional analysis of the ezrin-binding site in the hyaluronan receptor, CD44. Curr. Biol. 8, 705-708 (1998)

100. Legg J. W., C. A. Lewis, M. Parsons, T. Ng & C. M. Isacke: A novel PKC-regulated mechanism controls CD44-ezrin association and directional motility. Nat. Cell Biol. 4, 399-407 (2002)

101. Schneider-Schaulies J., L. M. Dunster, R. Schwartz-Albiez, G. Krohne & V. ter Meulen: Physical association of moesin and CD46 as a receptor complex for measles virus. J. Virol. 69, 2248-2256 (1995)

102. Reczek D., M. Berryman & A. Bretscher: Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J. Cell Biol. 139, 169-179 (1997)

103. Zhang M., S. S. Bohlson, M. Dy & A. J. Tenner: Modulated interaction of the ERM protein, moesin, with CD93. Immunol. 115, 63-73 (2005)

104. Yun C. H., G. Lamprecht, D. V. Forster & A. Sidor: NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. J. Biol. Chem. 273, 25856-25863 (1998)

105. Heiska L., A. Alfthan, M. Gronholm, P. Vilja, A. Vaheri & O. Carpen: Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 273, 21893-21900 (1998)

106. Ivetic A., J. Deka, A. Ridley & A. Ager: The cytoplasmic tail of L-selectin interacts with members of the Ezrin-Radixin-Moesin (ERM) family of proteins: cell activation-dependent binding of Moesin but not Ezrin. J. Biol. Chem. 277, 2321-2329 (2002)

107. Mykkanen O. M., M. Gronholm, M. Ronty, M. Lalowski, P. Salmikangas, H. Suila & O. Carpen: Characterization of human palladin, a microfilament-associated protein. Mol. Biol. Cell 12, 3060-3073 (2001)

108. Granes F., J. M. Urena, N. Rocamora & S. Vilaro: Ezrin links syndecan-2 to the cytoskeleton. J. Cell Sci. 113, 1276 (2000)

109. Granes F., C. Berndt, C. Roy, P. Mangeat, M. Reina & S. Vilaro: Identification of a novel Ezrin-binding site in syndecan-2 cytoplasmic domain. FEBS Lett. 547, 212-216 (2003)

110. Sun F., M. J. Hug, N. A. Bradbury & R. A. Frizzell: Protein kinase A associates with cystic fibrosis transmembrane conductance regulator via an interaction with ezrin. J. Biol. Chem 275, 14360-14366 (2000)

111. Denker S. P., D. C. Huang, J. Orlowski, H. Furthmayr & D. L. Barber: Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Molec. Cell 6, 1425-1436 (2000)

112. Maeda M., T. Matsui, M. Imamura, S. Tsukita & S. Tsukita: Expression level, subcellular distribution and rho-GDI binding affinity of merlin in comparison with Ezrin/Radixin/Moesin proteins. Oncogene 18, 4788-4797 (1999)

113. Cao X., X. Ding, Z. Guo, R. Zhou, F. Wang, F. Long, F. Wu, F. Bi, Q. Wang, D. Fan, J. G. Forte, M. Teng & X. Yao: PALS1 specifies the localization of ezrin to the apical membrane of gastric parietal cells. J Biol Chem 280, 13584-13592 (2005)

Key Words: Ezrin, Radixin, Moesin, ERM, T cells activation, Immunological Synapse, Actin Cytoskeleton, T lymphocyte Polarization, TCR, Review

Send correspondence to: Dr Andres Alcover, Unite de Biologie Cellulaire des Lymphocytes, Institut Pasteur, 25, rue Dr Roux, 75724, Paris, Cedex 15, France, Tel: 33-1-40-61-30-64, Fax: 33-1-40-61-32-38, E-mail: aalcover@pasteur.fr