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

Abstract

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. Tsuki