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ERM proteins and merlin: integrators at the cell cortex

Nature Reviews Molecular Cell Biology volume 3, pages 586–599 (2002)Cite this article

Key Points

  • The ERM (ezrin–radixin–moesin) proteins and merlin (the product of the neurofibromatosis II tumor-suppressor gene) contain a FERM (Four-point one, ezrin, radixin, moesin) at their amino terminus, and represent one class of the FERM domain superfamily. Phylogenetic analysis indicates that FERM domains evolved in response to multicellularity, rather than as cytoskeletal proteins.

  • Studies in Drosophila melanogaster and mice indicate that merlin provides an essential function, and that the single ERM protein Drosophila is also essential. However, in vertebrates, the presence of the three closely related ERM proteins complicates analysis. Nevertheless, transfection studies in cultured cells have implicated ERM proteins in microfilament–membrane attachment and Rho-signal-transduction pathways.

  • ERM proteins and merlin are negatively regulated by an intramolecular interaction between the amino- and carboxy-terminal domains. The interaction masks at least some of the binding sites in each domain, and can be relieved by carboxy-terminal phosphorylation in combination with acidic phospholipids, including phosphatidylinositol 4,5-bisphosphate.

  • The FERM domain of ERM proteins binds directly to the cytoplasmic region of several specific membrane proteins, as well as indirectly through the apical scaffolding proteins ERM-binding phosphoprotein 50 (EBP50)/sodium–hydrogen exchanger type 3 kinase A regulatory protein (E3KARP) to the tail of other membrane proteins. The FERM domain also binds to signalling molecules in the Rho pathway, including Rho guanine dinucleotide dissociation domain (Rho-GDI). An F-actin binding site is present in the carboxy-terminal domain of ERM proteins. So far, the F-actin binding site and sites for interaction with EBP50 and RhoGDI have been shown to be masked in the dormant, inactive monomer.

  • Merlin does not have a carboxy-terminal F-actin binding site, but its N-terminal domain binds many of the same proteins that interact with the ERM FERM domain, and also some distinct ones, such as the hepatocyte growth factor-regulated substrate (HRS).

  • The intramolecular regulatory interaction in merlin is also regulated by phosphorylation. This regulation might be crucial in transducing a high cell density signal from CD44, the receptor for hyaluronate, to dephosphorylate merlin and restrict proliferation. This regulation might be mediated through inhibition of the Rac pathway.

Abstract

A fundamental property of many plasma-membrane proteins is their association with the underlying cytoskeleton to determine cell shape, and to participate in adhesion, motility and other plasma-membrane processes, including endocytosis and exocytosis. The ezrin–radixin–moesin (ERM) proteins are crucial components that provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways. The closely related tumour suppressor merlin shares many properties with ERM proteins, yet also provides a distinct and essential function.

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Figure 1: ERM proteins contribute to the functional organization of specific plasma-membrane domains. Examples of three cell types are shown.
Figure 2: Localization of ERM proteins and merlin.
Figure 3: Domain relationships between erythrocyte band 4.1, the ERM family and merlin.
Figure 4: A model for the activation and function of the ERM proteins.

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Acknowledgements

We thank D. Chambers for Figure 2a, and B. McCartney for Figure 2b–f. Work in the authors' laboratories was supported by grants from the NIH (A.B. and R.G.F.) and the US Army Neurofibromatosis Research Program (R.G.F.).

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Cornell University, Ithaca, 14853, New York, USA

    Anthony Bretscher

  2. Department of Biological Sciences, Illinois State University, Normal, 61790, Illinois, USA

    Kevin Edwards

  3. Department of Biology, Developmental, Cell and Molecular Biology Group, Duke University, Durham, 27708, North Carolina, USA

    Richard G. Fehon

Authors
  1. Anthony Bretscher
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  2. Kevin Edwards
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  3. Richard G. Fehon
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Corresponding authors

Correspondence to Anthony Bretscher, Kevin Edwards or Richard G. Fehon.

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DATABASES

FlyBase

expanded

Interpro

ankyrin repeat region

myosin motor domain

PH

protein tyrosine phosphatase domain

RING finger

WW domain

OMIM

Neurofibromatosis type 2

Swiss-Prot

β-adrenergic receptor

cystic fibrosis transmembrane conductance regulator

CD44

E3KARP

ezrin

hamartin

ICAM-2

Jak3

moesin

Nf2

NHE-1

NHE-3

radixin

RhoGDI

vinculin

FURTHER READING

The Biology Workbench (for CLUSTALW and DRAWTREE)

Glossary

APICAL DOMAIN

The area of an epithelial cell that faces the lumen.

BASOLATERAL DOMAIN

The area of an epithelial cell that adjoins underlying tissue.

MICROVILLI

Small, finger-like projections (1–2 μm long and 100 nm wide) that occur on the exposed surfaces of epithelial cells to maximize the surface area.

MEMBRANE RUFFLES

Processes that are formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.

ADHERENS JUNCTION

A cell–cell and cell–extracellular-matrix adhesion complex that is composed of integrins and cadherins that are attached to cytoplasmic actin filaments.

BILE CANALICULUS

A groove on the surface of the liver cell that acts as a collecting system for bile that is made by the cell.

GLYCOSAMINOGLYCANS

Heteropolysaccharides that contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages that consist of either N-acetylglucosamine or N-acetylgalactosamine.

F-ACTIN

(Filamentous actin). A flexible, helical polymer of G-actin (globular actin) monomers that is 5–9 nm in diameter.

CYTOKINESIS

The process of cytoplasmic division.

PHAGOCYTOSIS

An actin-dependent process, by which cells engulf external particulate material by extension and fusion of pseudopods.

PHYLOGENETIC ANALYSIS

The study of evolutionary relationships among organisms.

PHOSPHOROTHIOATE ANTISENSE OLIGONUCLEOTIDES

Short, non-degradable antisense oligonucleotides that bind to specific messenger RNAs and suppress their translation, which inhibits synthesis of specific proteins.

DOMINANT-NEGATIVE

The effect of a defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

PARALOGUES

Homologous genes that originated by gene duplication (for example, human α-globin and human β-globin).

SCHWANN CELLS

Cells that produce myelin and ensheath axons in the peripheral nervous system.

BLOT OVERLAY

A method used to detect specific protein–protein interactions; protein mixtures are separated by gel electrophoresis, transferred to a membrane and then probed with a labelled test protein. The test protein binds its specific partner on the membrane and can then be detected by its label.

PLATELET

The smallest blood cell, which is important in haemostasis and blood coagulation.

NEOMYCIN

An antibiotic complex that binds polyphosphoinositides.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidyl-inositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

SCAFFOLDING PROTEIN

A protein that has specific binding sites and is therefore important in the assembly, structure and function of larger molecular complexes.

PDZ DOMAIN

Protein interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (Psd-95, discs-large and ZO-1).

NATURAL KILLER CELLS

A class of lymphocytes that are crucial in the innate immune response. They exert a cytotoxic activity on target cells (for example, virus-infected cells) that is enhanced by cytokines such as interferons.

IMMUNOLOGICAL SYNAPSE

A tight junction between T lymphocytes and target cells.

ANTIGEN-PRESENTING CELL

A cell, most often a macrophage or dendritic cell, that presents an antigen to activate a T cell.

GREEN-FLUORESCENT PROTEIN

An autofluorescent protein that was originally identified in the jellyfish Aequorea victoria.

FOCAL CONTACT

A small cellular structure that is associated with lamellipodia and pseudopods, in which the extracellular matrix on the outside of the cell is linked to the actin cytoskeleton on the inside of the cell.

PODOCYTE

A fenestrated cell that forms the visceral layer of the Bowman's capsule in the kidneys.

GTPγS

A non-hydrolysable analogue of GTP.

STRESS FIBRES

Axial bundles of F-actin that underlie the cell bodies.

YEAST TWO-HYBRID

A technique used to test if two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

LYSOPHOSPHATIDIC ACID

(LPA). Any phosphatidic acid that is deacylated at positions 1 or 2. It binds to a G-protein-coupled receptor, which results in the activation of the small GTP-binding protein Rho and the induction of stress fibres.

COILED-COIL DOMAINS

A protein domain that forms a bundle of two or three α-helices. Whereas short coiled-coil domains are involved in protein interactions, long coiled-coil domains that form long rods occur in structural or motor proteins.

CRE/LOXP

A site-specific recombination system that is derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

HYPERPLASIA

An increase in the number of cells in a tissue or organ without gross morphological changes.

FLP/FLT

Flp encodes a recombinase that catalyses site-specific recombination between sites called Flp recognition targets (FRT). The Flp/FRT system has been successfully applied as a site-specific recombination system.

Rho FAMILY GTPases

Ras-related GTPases that are involved in controlling the organization of actin.

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Bretscher, A., Edwards, K. & Fehon, R. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3, 586–599 (2002). https://doi.org/10.1038/nrm882

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