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Organizing the cell cortex: the role of ERM proteins

Nature Reviews Molecular Cell Biology volume 11, pages 276–287 (2010)Cite this article

Subjects

An Erratum to this article was published on 30 July 2010

Key Points

  • Ezrin, radixin and moesin, the ERMs, have a key role in organizing specialized membrane domains through their ability to interact with transmembrane proteins, membrane-associated cytoplasmic proteins and filamentous actin.

  • ERM activity is regulated through head to tail folding, which in turn is regulated by phospholipid binding and phosphorylation. Structural studies indicate that known interaction sites are inaccessible in the fully folded state, although the data suggest that phospholipid binding may displace the linker region between the head and tail domains, thereby initiating unfolding and activation of ERMs.

  • Genetic studies of ERMs have now been carried out in flies, worms and mice, revealing a wealth of functions in polarized epithelial cells, mitotic cells and the developing oocyte. In addition, recent studies in mammalian cultured cells using genetic tools such as short hairpin RNA-mediated knockdown, have added to our understanding of ERM function in the immune system and disease.

  • Experiments in various systems have implicated ERMs as both regulators and downstream targets of RhoA signalling. Studies in flies suggest that ERMs function antagonistically to RhoA, whereas most studies in mammalian systems have suggested that ERMs promote RhoA signalling.

  • Studies in flies indicate that ERMs are important for epithelial integrity, in part because of their role in organizing apical actin and in part because of their ability to regulate RhoA function.

  • In worms and mice, genetic experiments indicate an essential role for ERMs in lumen morphogenesis. In both cases, the ability to form a free apical domain bordered by a junctional complex seems to be compromised in the absence of ERM function.

  • In the immunological synapse, which forms between antigen-presenting cells and T cells, ERM function is modulated to disassemble microvilli and alter the abundance and localization of several transmembrane proteins. This system also provides clear evidence of functional diversification between the three ERMs. A similar structure, termed the virological synapse, has been described at the site where HIV-1 infects lymphocytes.

  • Recent work has revealed roles for ERMs in tumour metastasis, although the mechanistic basis of this function is not yet understood.

Abstract

Specialized membrane domains are an important feature of almost all cells. In particular, they are essential to tissues that have a highly organized cell cortex, such as the intestinal brush border epithelium. The ERM proteins (ezrin, radixin and moesin) have a crucial role in organizing membrane domains through their ability to interact with transmembrane proteins and the cytoskeleton. In doing so, they can provide structural links to strengthen the cell cortex and regulate the activities of signal transduction pathways. Recent studies examining the structure and in vivo functions of ERMs have greatly advanced our understanding of the importance of membrane–cytoskeleton interactions.

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Figure 1: Domain organization of ERMs and an activation model.
Figure 2: Structures of FERM domains with bound ligands.
Figure 3: In vivo functions of ERMs.

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Acknowledgements

We thank the members of our laboratories for their contributions and helpful discussions. We apologize for work that was omitted owing to space limitations. Work in our laboratories was supported by grants from the National Institutes of Health (A.B., R.G.F. and A.I.M.) and the US Army Neurofibromatosis Research Program (A.B. and A.I.M.).

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Authors and Affiliations

  1. Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, 60637, Illinois, USA

    Richard G. Fehon

  2. Department of Pathology, Massachusetts General Hospital Center for Cancer Research and Harvard Medical School, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Andrea I. McClatchey

  3. Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, New York, USA

    Anthony Bretscher

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DATABASES

Protein Data Bank

1EF1

1J19

1SGH

2I1J

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Glossary

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an APC with which it is interacting. It consists of molecules required for adhesion and signalling, is important in establishing T cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

PDZ domain

(Postsynaptic density protein of 95 kDa, Discs large and Zonula occludens 1 domain). A region that is present in several scaffolding proteins and is named after the founding members of this protein family. PDZ domains bind to specific short amino acid sequences in interacting proteins.

Hypomorphic

A mutant allele that has a similar but weaker function than the wild-type allele.

Juxtamembrane region

A sequence in a transmembrane protein on the cytoplasmic side that is adjacent to a transmembrane helix.

Adherens junction

A cell–cell adhesion complex that contains cadherins and catenins that are associated with cytoplasmic actin filaments.

Atomic force microscope

A microscope that non-destructively measures the forces (at the atomic level) between a sharp probing tip (which is attached to a cantilever spring) and a sample surface. The microscope images structures at the resolution of individual atoms.

Imaginal disc

A single-cell layer epithelial structure of the D. melanogaster larva that gives rise to wings, legs and other appendages.

Brush border

The highly architecturally and functionally specialized apical domain of intestinal and renal epithelial cells. It is composed of the cytoskeleton-rich terminal web and its associated apical junctions, which form a platform from which a dense array of microvilli project. These microvilli increase the absorptive and resorptive surface areas of the gut and kidney, respectively.

Syncytial embryo

The early stage D. melanogaster embryo, in which a rapid series of nuclear replication cycles occur in the absence of cell division, resulting in a single cell with thousands of nuclei.

Synaptotagmin

One of a group of Ca2+-binding proteins that are generally understood to be involved with the secretion of granules and vesicles, especially in the nervous system.

Apical polarity complex

A protein complex consisting of PAR3 (known as Bazooka in D. melanogaster), PAR6 and atypical protein kinase C that establishes and maintains the apical membrane in polarized epithelial cells.

Epithelial to mesenchymal transformation

A morphological change that is characteristic of some developing tissues and certain forms of cancer, in which cells lose intercellular junctions and apical–basal polarity, become migratory and, in the case of cancer, become invasive.

Cadherin

A cell-type-specific calcium-dependent transmembrane adhesion protein. Cadherins promote homophilic binding and are preferentially located at adherens junctions.

Catenin

A cytoplasmic protein that is directly or indirectly linked to the cytoplasmic tail of cadherins. In this complex, catenins promote the anchoring of cadherins to actin and junction stabilization.

Osteosarcoma

A malignant tumour of the osteoid bone.

Rhabdomyosarcoma

A malignant tumour of skeletal muscle.

Podocyte

A cell in the kidney that has a crucial function in the filtration of solutes in the blood to form urine.

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Fehon, R., McClatchey, A. & Bretscher, A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol 11, 276–287 (2010). https://doi.org/10.1038/nrm2866

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