Cortical Actin Organization: Lessons from ERM (Ezrin/Radixin/Moesin) Proteins

ezrin/radixin/moesin ERM-binding phosphoprotein of 50 kDa protein-tyrosine phosphatase Na+/H+ exchanger regulatory factor protein kinase A ERM-association domain phosphatidylinositol 4,5-bisphosphate guanosine 5′-O-(3-thio)triphosphate phosphatidylinositol 4-phosphate 5-kinase GDP dissociation inhibitor In recent years to clarify the molecular mechanism of dynamic organization of the cortical actin filaments, which is important not only for the determination of cell-surface structures but also for the functions of integral membrane proteins themselves, various types of submembrane proteins involved in cortical actin filament/plasma membrane interaction have been intensively studied. In this minireview, we focus on ezrin/radixin/moesin (ERM)1 proteins, which are general cross-linkers between cortical actin filaments and plasma membranes and are involved in the formation of microvilli, cell adhesion sites, ruffling membranes, and cleavage furrows. ERM proteins have attracted a great deal of interest because their functions have been shown to be regulated by the Rho signaling pathway (for recent reviews, see Refs. 1Bretscher A. Reczek D. Berryman M. J. Cell Sci. 1997; 110: 3011-3018Crossref PubMed Google Scholar, 2Tsukita Sa Yonemura S. Tsukita Sh Curr. Opin. Cell Biol. 1997; 9: 70-75Crossref PubMed Scopus (313) Google Scholar, 3Tsukita Sa Yonemura S. Tsukita Sh Trends Biochem. Sci. 1997; 22: 53-58Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 4Vaheri A. Carpén O. Heiska L. Helander T.S. Jääskeläinen J. Majander-Nordenswan P. Sainio M. Timonen T. Turunen O. Curr. Opin. Cell Biol. 1997; 9: 659-666Crossref PubMed Scopus (165) Google Scholar, 5del Pozo M.A. Nieto M. Serrador J.M. Sancho D. Vicente-Manzanares M. Martinez C. Sanchez-Madrid F. Cell Adhes. Commun. 1998; 6: 125-133Crossref PubMed Scopus (68) Google Scholar, 6Bretscher A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 7Mangeat P. Roy C. Martin M. Trends Cell Biol. 1999; 9: 187-192Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). The ERM family consists of three closely related proteins, ezrin, radixin, and moesin (ERM proteins) (8Sato N. Funayama N. Nagafuchi A. Yonemura S. Tsukita Sa Tsukita Sh J. Cell Sci. 1992; 103: 131-143PubMed Google Scholar) (Fig.1). Ezrin (∼82 kDa) was first isolated from chicken intestinal brush borders as a component of microvilli (9Bretcher A. J. Cell Biol. 1983; 97: 425-432Crossref PubMed Scopus (256) Google Scholar). Molecular cloning revealed that ezrin was identical to cytovillin, which was enriched in microvilli of human placental syncytiotrophoblasts (10Gould K.L. Bretscher A. Esch F.S. Hunter T. EMBO J. 1989; 8: 4133-4142Crossref PubMed Scopus (244) Google Scholar, 11Turunen O. Winqvist R. Pakkanen R. Grzeschik K.-H. Wahlström T. Vaheri A. J. Biol. Chem. 1989; 264: 16727-16732Abstract Full Text PDF PubMed Google Scholar). Radixin (∼80 kDa) was isolated from rat liver as a component of adherens junctions (12Tsukita Sa Hieda Y. Tsukita Sh J. Cell Biol. 1989; 108: 2369-2382Crossref PubMed Scopus (187) Google Scholar). Moesin (∼75 kDa) was isolated from bovine uterus abundant in smooth muscle cells as a heparin-binding protein (13Lankes W. Griesmacher A. Grünwald J. Schwartz-Albiez R. Keller R. Biochem. J. 1988; 251: 831-842Crossref PubMed Scopus (117) Google Scholar). Homologues for ERM proteins have been found from Caenorhabditis elegans to human, although the number of family members appears to vary from one to three depending on species (2Tsukita Sa Yonemura S. Tsukita Sh Curr. Opin. Cell Biol. 1997; 9: 70-75Crossref PubMed Scopus (313) Google Scholar). The sequences of their N-terminal halves are highly conserved (∼85% identity) and similar to the N-terminal half of human erythroid band 4.1 protein (∼78 kDa), indicating that the ERM family is included in the band 4.1 superfamily that contains merlin/schwannomin (a tumor suppressor molecule for neurofibromatosis type II), talin, PTP-H1, and PTP-MEG. Among these, merlin (isoforms I–III)(∼70 kDa) is fairly similar to ERM proteins (∼60% identity). The sequence, which is conserved among the members of the band 4.1 superfamily and referred to as the FERM (4.1 and ERM) domain, is a membrane-binding site in band 4.1 protein, and similar sequences have recently been found in the central portion of PTP-BAS and the C-terminal domain of myosin VIIA. In ERM proteins, the N-terminal FERM domain is followed by an extended α-helical domain and a charged C-terminal domain, which includes a consensus sequence motif for actin binding. Thus, from their structure, ERM proteins have been suggested to function as cross-linkers between actin filaments and plasma membranes (1Bretscher A. Reczek D. Berryman M. J. Cell Sci. 1997; 110: 3011-3018Crossref PubMed Google Scholar, 2Tsukita Sa Yonemura S. Tsukita Sh Curr. Opin. Cell Biol. 1997; 9: 70-75Crossref PubMed Scopus (313) Google Scholar, 3Tsukita Sa Yonemura S. Tsukita Sh Trends Biochem. Sci. 1997; 22: 53-58Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 4Vaheri A. Carpén O. Heiska L. Helander T.S. Jääskeläinen J. Majander-Nordenswan P. Sainio M. Timonen T. Turunen O. Curr. Opin. Cell Biol. 1997; 9: 659-666Crossref PubMed Scopus (165) Google Scholar, 5del Pozo M.A. Nieto M. Serrador J.M. Sancho D. Vicente-Manzanares M. Martinez C. Sanchez-Madrid F. Cell Adhes. Commun. 1998; 6: 125-133Crossref PubMed Scopus (68) Google Scholar, 6Bretscher A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 7Mangeat P. Roy C. Martin M. Trends Cell Biol. 1999; 9: 187-192Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Immunoblotting analysis and immunofluorescence microscopy revealed that in most cultured cells all ERM proteins are co-expressed and co-localized but that in organs their expression and distribution pattern appear to be regulated in a cell type-specific manner (1Bretscher A. Reczek D. Berryman M. J. Cell Sci. 1997; 110: 3011-3018Crossref PubMed Google Scholar, 2Tsukita Sa Yonemura S. Tsukita Sh Curr. Opin. Cell Biol. 1997; 9: 70-75Crossref PubMed Scopus (313) Google Scholar, 3Tsukita Sa Yonemura S. Tsukita Sh Trends Biochem. Sci. 1997; 22: 53-58Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 4Vaheri A. Carpén O. Heiska L. Helander T.S. Jääskeläinen J. Majander-Nordenswan P. Sainio M. Timonen T. Turunen O. Curr. Opin. Cell Biol. 1997; 9: 659-666Crossref PubMed Scopus (165) Google Scholar, 5del Pozo M.A. Nieto M. Serrador J.M. Sancho D. Vicente-Manzanares M. Martinez C. Sanchez-Madrid F. Cell Adhes. Commun. 1998; 6: 125-133Crossref PubMed Scopus (68) Google Scholar, 6Bretscher A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 7Mangeat P. Roy C. Martin M. Trends Cell Biol. 1999; 9: 187-192Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Immunofluorescence studies of cultured fibroblasts and epithelial cells have revealed that ERM proteins are co-expressed and co-concentrated at cell-surface structures such as microvilli, filopodia, uropods, ruffling membranes, retraction fibers, and cell adhesion sites where actin filaments are associated with plasma membranes (8Sato N. Funayama N. Nagafuchi A. Yonemura S. Tsukita Sa Tsukita Sh J. Cell Sci. 1992; 103: 131-143PubMed Google Scholar, 14Sato N. Yonemura S. Obinata T. Tsukita Sa Tsukita Sh J. Cell Biol. 1991; 113: 321-330Crossref PubMed Scopus (115) Google Scholar, 15Franck Z. Gary R. Bretscher A. J. Cell Sci. 1993; 105: 219-231Crossref PubMed Google Scholar, 16Amieva M.R. Furthmayr H. Exp. Cell Res. 1995; 219: 180-196Crossref PubMed Scopus (132) Google Scholar, 17Serrador J.M. Alonso-Lebrero J.L. del Pozo M.A. Furthmayr H. Schwartz-Albiez R. Calvo J. Lozano F. Sánchez-Madrid F. J. Cell Biol. 1997; 138: 1409-1423Crossref PubMed Scopus (205) Google Scholar) (Fig.2). ERM proteins are also concentrated specifically at cleavage furrows in dividing cells (14Sato N. Yonemura S. Obinata T. Tsukita Sa Tsukita Sh J. Cell Biol. 1991; 113: 321-330Crossref PubMed Scopus (115) Google Scholar) but not along cytoplasmic actin filaments such as stress fibers, in contrast to filamin and α-actinin, which are concentrated in both sites (18Nunnally M.H. D'Angelo J.M. Graig S.W. J. Cell Biol. 1980; 87: 219-226Crossref PubMed Scopus (66) Google Scholar). Suppression of the expression of all ERM proteins with antisense oligonucleotides in cultured fibroblasts/epithelial cells destroyed microvillus formation as well as cell-to-cell/cell-to-substrate adhesion (19Takeuchi K. Sato N. Kasahara H. Funayama N. Nagafuchi A. Yonemura S. Tsukita Sa Tsukita Sh J. Cell Biol. 1994; 125: 1371-1384Crossref PubMed Scopus (326) Google Scholar). Similarly, in cultured neurons that contain mainly radixin and moesin, antisense oligonucleotides of radixin and moesin severely affected the morphology, motility, and process formation of growth cones (20Paglini G. Kunda P. Quiroga S. Kosik K. Cáceres A. J. Cell Biol. 1998; 143: 443-455Crossref PubMed Scopus (142) Google Scholar). Specific ezrin ablation by MicroCALI (chromatophore-assisted laser irradiation) blocked membrane ruffling and motility (21Lamb R.F. Ozanne B.W. Roy C. McGarry L. Stipp C. Mangeat P. Jay D.G. Curr. Biol. 1997; 7: 682-688Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). Furthermore, overproduction of full-length ERM proteins appeared to enhance cell adhesion, whereas that of their C-terminal halves perturbed the cell-surface morphology and inhibited cytokinesis (22Martin M. Andréoli C. Sahuquet A. Montcourrier P. Algrain M. Mangeat P. J. Cell Biol. 1995; 128: 1081-1093Crossref PubMed Scopus (122) Google Scholar, 23Henry M.D. Agosti C.G. Solomon F. J. Cell Biol. 1995; 129: 1007-1022Crossref PubMed Scopus (99) Google Scholar). These findings suggested that ERM proteins were involved in the formation and/or maintenance of cortical actin organization through their cross-linking activity between actin filaments and plasma membranes. Extensive functional analyses suggested the possible functional redundancy of ERM proteins at least at the cellular level. Recently, moesin-deficient mice were generated by gene targeting, and they appeared normal without any compensatory up-regulation of ezrin or radixin (24Doi Y. Itoh M. Yonemura S. Ishihara S. Takano H. Noda T. Tsukita Sh Tsukita Sa J. Biol. Chem. 1999; 274: 2315-2321Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Therefore, also at the whole body level ERM proteins appear to be functionally redundant, although ERM proteins are not necessarily co-localized and co-expressed at the organ level. Targeted disruption of ezrin and radixin genes will allow clarification of this redundancy problem in the near future. The C-terminal halves of ERM proteins bind to F-actin through their major actin-binding sites, the C-terminal 34 amino acids, which are highly conserved among these proteins (25Turunen O. Wahlström T. Vaheri A. J. Cell Biol. 1994; 126: 1445-1453Crossref PubMed Scopus (356) Google Scholar). In addition to this domain, two more actin-binding domains have recently been identified in their N-terminal and middle regions, which bind to F-actin and both F- and G-actin, respectively (26Roy C. Martin M. Mangeat P. J. Biol. Chem. 1997; 272: 20088-20095Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Although the physiological relevance of these newly identified actin-binding sites in ERM proteins is not clear at present, the mode of association of actin filaments with ERM proteins does not appear to be simple. G-actin binding affinity in their middle regions would explain the actin barbed end-capping activity of ERM proteins, which was detected in radixin at low ionic strength (12Tsukita Sa Hieda Y. Tsukita Sh J. Cell Biol. 1989; 108: 2369-2382Crossref PubMed Scopus (187) Google Scholar). On the other hand, the N-terminal halves of ERM proteins were reported to directly bind to the cytoplasmic domains of CD44 (27Tsukita Sa Oishi K. Sato N. Sagara J. Kawai A. Tsukita Sh J. Cell Biol. 1994; 126: 391-401Crossref PubMed Scopus (704) Google Scholar, 28Hirao M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar) and other integral membrane proteins such as ICAM-1, -2, and -3 and CD43, which were co-localized with ERM proteins in vivo (17Serrador J.M. Alonso-Lebrero J.L. del Pozo M.A. Furthmayr H. Schwartz-Albiez R. Calvo J. Lozano F. Sánchez-Madrid F. J. Cell Biol. 1997; 138: 1409-1423Crossref PubMed Scopus (205) Google Scholar, 27Tsukita Sa Oishi K. Sato N. Sagara J. Kawai A. Tsukita Sh J. Cell Biol. 1994; 126: 391-401Crossref PubMed Scopus (704) Google Scholar, 28Hirao M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar, 29Helander T.S. Carpén O. Turunen O. Kovanen P.E. Vaheri A. Timmonen T. Nature. 1996; 382: 265-268Crossref PubMed Scopus (201) Google Scholar, 30Heiska L. Alfthan K. Grönholm M. Vilja P. Vaheri A. Carpén O. J. Biol. Chem. 1998; 273: 21893-21900Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 31Yonemura S. Nagafuchi A. Sato N. Tsukita Sh J. Cell Biol. 1993; 120: 437-449Crossref PubMed Scopus (140) Google Scholar, 32Yonemura S. Hirao M. Doi Y. Takahashi N. Kondo T. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: 885-895Crossref PubMed Scopus (514) Google Scholar). Although the cytoplasmic domains of these integral membrane proteins have no shared sequences, their juxtamembrane positively charged amino acid clusters are thought to be responsible for their binding to ERM proteins (32Yonemura S. Hirao M. Doi Y. Takahashi N. Kondo T. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: 885-895Crossref PubMed Scopus (514) Google Scholar, 33Legg J.W. Isacke C.M. Curr. Biol. 1998; 8: 705-708Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). This direct binding of ERM proteins with integral membrane proteins was shown to be essential for cell-surface morphogenesis such as microvillus formation (34Yonemura S. Tsukita Sa Tsukita Sh J. Cell Biol. 1999; 145: 1497-1509Crossref PubMed Scopus (182) Google Scholar, 35Kenney D. Cairns L. Remold-O'Donnell E. Peterson J. Rosen F.S. Parkman R. Blood. 1986; 68: 1329-1332Crossref PubMed Google Scholar). Ezrin effected the function of ICAM-2 in thymoma cells for being targeted by natural killer cells (29Helander T.S. Carpén O. Turunen O. Kovanen P.E. Vaheri A. Timmonen T. Nature. 1996; 382: 265-268Crossref PubMed Scopus (201) Google Scholar). The mechanism of indirect binding of ERM proteins to integral membrane proteins has also been reported. EBP-50 (ERM-binding phosphoprotein of 50 kDa) was identified as a cytoplasmic protein, the C-terminal region of which binds to the N-terminal half of ezrin (36Reczek D. Berryman M. Bretscher A. J. Cell Biol. 1997; 139: 169-179Crossref PubMed Scopus (519) Google Scholar). Sequence analyses revealed that EBP-50 is identical to a Na+/H+exchanger regulatory factor (NHE-RF). This NHE-RF and its isoform, E3KARP, bear two PDZ domains, which were shown to directly bind to the C terminus of NHE3 (36Reczek D. Berryman M. Bretscher A. J. Cell Biol. 1997; 139: 169-179Crossref PubMed Scopus (519) Google Scholar, 37Reczek D. Bretscher A. J. Biol. Chem. 1998; 273: 18452-18458Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Thus, NHE-RF and E3KARP can function as adapters between NHE3 and ezrin (38Dransfield D.T. Bradford A.J. Smith J. Martin M. Roy C. Mangeat P.H. Goldenring J.R. EMBO J. 1997; 16: 35-43Crossref PubMed Scopus (270) Google Scholar). Interestingly, because NHE-RF regulates the NHE3 function in a protein kinase A (PKA)-dependent manner and because ezrin specifically binds to the RII subunit of PKA (38Dransfield D.T. Bradford A.J. Smith J. Martin M. Roy C. Mangeat P.H. Goldenring J.R. EMBO J. 1997; 16: 35-43Crossref PubMed Scopus (270) Google Scholar), ezrin appears to play an important role in recruiting PKA to the NHE3·NHE-RF complex to regulate the function of NHE3. Furthermore, NHE-RF and E3KARP were found to also be associated with other integral membrane proteins such as the β2-adrenergic receptor and the cystic fibrosis transmembrane conductance regulator (39Hall R.A. Premont R.T. Chow C.-W. Blitzer J.T. Pitcher J.A. Claing A. Stoffel R.H. Barak L.S. Shenolikar S. Weinman E.J. Grinstein S. Lefkowitz R.J. Nature. 1998; 392: 626-630Crossref PubMed Scopus (524) Google Scholar, 40Short D.B. Trotter Reczek D. Bretscher A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), which are not co-localized with ERM proteins J. D. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). The physiological relevance of the of two of binding of ERM proteins to integral membrane proteins, direct and is an for that the cortical actin filaments are in to various the cross-linking activity of ERM proteins between actin filaments and plasma membranes is to be the by Bretscher A. J. Cell Biol. 1989; 108: PubMed Scopus Google Scholar) or T. A. J. 1989; PubMed Google Scholar) that of cells or the of cells of ERM proteins to the cortical actin with of ERM cultured cells were and in physiological ERM proteins were the and T. K. Doi Y. Yonemura S. S. Tsukita Sh Tsukita Sa J. Cell Biol. 1997; 139: PubMed Scopus Google Scholar). These findings suggested that are and of ERM proteins in of their cross-linking activity has in and in the and C-terminal halves of ERM proteins and their actin and membrane binding respectively C. Martin M. R. H. Mangeat P. J. Cell Sci. 1994; Google Scholar, R. Bretscher A. Biol. 1995; 6: PubMed Scopus Google Scholar, M. M.D. A. Solomon F. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). Recently, was shown that two amino acid were from the C-terminal of ezrin, which not to the domain, the interaction was ezrin to directly with EBP-50 D. Bretscher A. J. Biol. Chem. 1998; 273: 18452-18458Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). These findings that by interaction is the molecular mechanism the of ERM The region involved in the interaction was to and and is as in ezrin, and these regions are and respectively R. Bretscher A. Biol. 1995; 6: PubMed Scopus Google Scholar). these and were thought to be responsible for of ERM proteins, interaction of ERM proteins, but has been suggested that they are also important for interaction A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 7Mangeat P. Roy C. Martin M. Trends Cell Biol. 1999; 9: 187-192Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Furthermore, analyses identified middle regions between and that with and Goldenring J.R. Biochem. Res. Commun. 1998; PubMed Scopus Google Scholar). Although the molecular mechanism and physiological relevance of and of ERM proteins is that the mechanism ERM proteins in an and that this to ERM proteins two molecular have been shown to and/or the of ERM proteins in of their C-terminal and binding to their N-terminal The of ERM proteins, ezrin, has been in and of ezrin in cells with from the to the cortical actin A. J. Cell Biol. 1989; 108: PubMed Scopus Google Scholar). The that were in cells were shown to be and and is in ezrin, the of which was conserved in radixin and moesin J. Hunter T. 1992; Scholar). ERM proteins were also reported to be by and growth factor H. Nagafuchi A. Yonemura S. Tsukita Sa J. W. Tsukita Sh J. Cell Biol. 1995; PubMed Scopus Google Scholar, T. A. D. M. J. Cell Biol. 1997; 138: PubMed Scopus Google Scholar). the of with in ezrin on cell motility but not the cortical of ezrin by growth Thus, the direct of ERM proteins by is in cells was reported to of ezrin T. A. J. 1989; PubMed Google Scholar). In the of moesin at a C-terminal F. M.R. Furthmayr H. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), This site was in by in radixin and by T. M. Doi Y. Yonemura S. M. K. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: PubMed Scopus Google Scholar, A. L. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). is that not ERM proteins in vivo T. Yonemura S. Tsukita Sh Tsukita Sa Curr. Biol. 1999; 9: Full Text Full Text PDF PubMed Google Scholar). In analyses suggested that the C-terminal ERM proteins in the by the interaction T. M. Doi Y. Yonemura S. M. K. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: PubMed Scopus Google Scholar). Immunofluorescence microscopy with for C-terminal ERM proteins revealed that ERM proteins plasma membranes were at the C-terminal in vivo T. M. Doi Y. Yonemura S. M. K. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: PubMed Scopus Google Scholar, K. Yonemura S. T. Tsukita Sa Tsukita Sh J. Cell Sci. 1999; PubMed Google Scholar). all that the the ERM for the for ERM proteins is which has been shown to directly bind to the N-terminal halves of ERM proteins in M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar, Andréoli C. Roy C. Mangeat P. 1995; PubMed Scopus Google Scholar). Recently, has been shown that is a factor for the of ERM proteins in vivo T. Yonemura S. Tsukita Sh Tsukita Sa Curr. Biol. 1999; 9: Full Text Full Text PDF PubMed Google Scholar). The has as to the of the for of ERM one of the proteins, is to be a general regulator of in as well as in vivo analyses have suggested an between the Rho signaling pathway and of ERM the binding of ERM proteins to the cytoplasmic domain of CD44 in cell was reported to be by of Rho M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar). In at least one of the ERM proteins was shown to be for formation of stress and A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, of the of but not that of or microvillus formation to which ERM proteins were T. Yonemura S. Tsukita Sh Tsukita Sa Curr. Biol. 1999; 9: Full Text Full Text PDF PubMed Google Scholar, R.J. M. Solomon F. T. Biol. 1998; 9: PubMed Scopus Google Scholar). Thus, is that Rho is in ERM proteins in the are and to plasma membranes to Although ERM proteins are also suggested to be of A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), the of ERM proteins to microvilli specifically on Rho but not on Rho has been reported to such as protein kinase and protein kinase A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Immunoblotting with a for C-terminal ERM proteins revealed that in cells Rho by acid the of the C-terminal of ERM proteins T. M. Doi Y. Yonemura S. M. K. Tsukita Sa Tsukita Sh J. Cell Biol. 1998; 140: PubMed Scopus Google Scholar). which the C-terminal of ERM proteins in is not responsible for this of ERM proteins in phosphatidylinositol 4-phosphate 5-kinase has also been reported to be a direct Rho (for a see M.A. Curr. Opin. 1998; 8: PubMed Scopus Google Scholar). of ERM proteins was by in vivo as well M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar, T. Yonemura S. Tsukita Sh Tsukita Sa Curr. Biol. 1999; 9: Full Text Full Text PDF PubMed Google Scholar), one possible pathway for the of ERM proteins is as Rho which in the of ERM proteins by their which of their C-terminal by The ERM proteins are as which function as actin filament/plasma membrane cross-linkers to microvilli On the other hand, identified dissociation in the protein complex M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita Sh Tsukita Sa J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (513) Google Scholar). binding revealed that but not of ERM proteins directly to at their N-terminal halves K. Sasaki T. A. K. T. Tsukita Sa Tsukita Sh Takai Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, this binding of ERM proteins activity of was from followed by as through K. Sasaki T. A. K. T. Tsukita Sa Tsukita Sh Takai Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, K. Sasaki T. A. K. H. K. A. Takai Y. 1998; 16: PubMed Scopus Google Scholar). These findings suggested that ERM proteins, can which ERM proteins as a In this ERM proteins are not only but also of of ERM proteins have a to by the the of ERM proteins at the of ERM proteins were and in their cytoplasmic with T. K. Doi Y. Yonemura S. S. Tsukita Sh Tsukita Sa J. Cell Biol. 1997; 139: PubMed Scopus Google Scholar). In this the C-terminal was to be by the for C-terminal ERM Recently, myosin phosphatase was shown to bind to moesin through its subunit in although its physiological relevance Y. K. N. H. Y. K. J. Cell Biol. 1998; PubMed Scopus Google Scholar). On the other hand, be of of ERM proteins because ezrin is a for in A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 7Mangeat P. Roy C. Martin M. Trends Cell Biol. 1999; 9: 187-192Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Although is on and and/or and their regulate the function of ERM but not of the of ERM proteins appear to be shared by The of ERM proteins was similar to that of merlin in fibroblasts and ruffling but in epithelial but not ERM proteins, was concentrated at membranes with M. T. M. Tsukita Sh Tsukita Sa 1999; PubMed Scopus Google Scholar). The N-terminal half of merlin to the cytoplasmic domains of CD44 M. F. Heiska L. Turunen O. M. E. M. Jääskeläinen J. Vaheri A. Carpén O. J. Cell Sci. 1997; 110: PubMed Google Scholar) and NHE-RF A. C. E. D. C. Solomon F. J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) as well as in M. T. M. Tsukita Sh Tsukita Sa 1999; PubMed Scopus Google Scholar). has two major and which at their C-terminal T. N. Res. 1994; Google Scholar). Although of these C-terminal any to of ERM proteins, the major actin-binding domains, merlin has been reported to bind to actin filaments at its middle region J. Res. 1998; PubMed Scopus (142) Google Scholar). interaction between the and C-terminal halves has been suggested in but the interaction does not appear to its binding affinity to actin filaments or to NHE-RF A. C. E. D. C. Solomon F. J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Res. 1998; PubMed Scopus (142) Google Scholar). interaction has been detected in L. R.T. S. N. H. P. 1997; PubMed Scopus (205) Google Scholar). present, are three possible for the sequence between ERM proteins and is possible that merlin functions in cells by for shared binding such as and because the of was to be in cultured fibroblasts and epithelial the is not in merlin would be functionally for ERM from the of ERM proteins by antisense oligonucleotides are with this Furthermore, this was not by the that mice an K. D. R.T. T. 1998; PubMed Scopus Google Scholar). is also possible that merlin sequence to ERM proteins because both are involved in Rho signaling for both bind to this is the of function of merlin through in the Rho signaling In this be that which is responsible for neurofibromatosis type protein activity for P. D. R. M. M. D. J. R. R. R. Full Text PDF PubMed Scopus Google Scholar). is to that both neurofibromatosis types and are by of signaling In the has been that ERM proteins function as general cross-linkers in the cortical with such as Rho ERM proteins are this cross-linking would be involved in various cellular in various types of Thus, in the ERM proteins will interest in from not only but also in the ERM proteins are thought to play an important role in cell of by (17Serrador J.M. Alonso-Lebrero J.L. del Pozo M.A. Furthmayr H. Schwartz-Albiez R. Calvo J. Lozano F. Sánchez-Madrid F. J. Cell Biol. 1997; 138: 1409-1423Crossref PubMed Scopus (205) Google Scholar, 29Helander T.S. Carpén O. Turunen O. Kovanen P.E. Vaheri A. Timmonen T. Nature. 1996; 382: 265-268Crossref PubMed Scopus (201) Google Scholar). will also be to the between ERM proteins and Radixin was as a protein in E. Solomon F. J. Cell Biol. 1989; PubMed Scopus Google Scholar), and in was co-concentrated at the with ERM proteins (17Serrador J.M. Alonso-Lebrero J.L. del Pozo M.A. Furthmayr H. Schwartz-Albiez R. Calvo J. Lozano F. Sánchez-Madrid F. J. Cell Biol. 1997; 138: 1409-1423Crossref PubMed Scopus (205) Google Scholar). Furthermore, was also shown that ERM proteins have with which is on the of and is for in Solomon F. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). studies of the ERM interaction will the physiological functions of ERM proteins as well as the cortical actin