Review
ERM proteins and NF2 tumor suppressor: the Yin and Yang of cortical actin organization and cell growth signaling

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Abstract

The ERM (ezrin, radixin and moesin) family of proteins are linkers that tether actin microfilaments to the plasma membrane. Merlin, the NF2 tumor suppressor gene product, is highly homologous to ERM proteins. In ERM proteins and merlin, interdomain binding promotes auto-inhibition and homo-oligomerization or hetero-oligomerization. Recent studies have revealed that ERM proteins transduce growth signals, and have shed new light on how merlin links cell growth to the cytoskeleton.

Introduction

The ERM (ezrin, radixin and moesin) family of proteins were originally characterized as structural components of the cell cortex. Merlin, also named schwannomin, was identified by genetic approaches aiming to characterize the molecular basis of neurofibromatosis 2 (NF2). This is an autosomal dominantly inherited disorder that predisposes the patient to the development of multiple benign tumors of the central nervous system, such as schwannomas and meningiomas. The NF2 gene is also implicated in the development of sporadic schwannomas and meningiomas, as well as mesotheliomas induced by asbestos [1]. ERM proteins and merlin display a similar structural organization. They share extensive homology in their amino-terminal domain, which is called the FERM domain. The carboxy-terminal domains of ERM proteins and of merlin are more distantly related. Merlin lacks a conserved actin C-terminal binding site present in ERM proteins [2]. Like ERM proteins, however, merlin contains actin binding sites in its amino-terminal domain 3., 4., 5•..

These proteins form intramolecular and intermolecular associations between their amino-terminal and carboxy-terminal domains, which are called N-ERM and C-ERM Association Domains (N-ERMADs and C-ERMADs, respectively) [6]. Intramolecular association causes the proteins to adopt closed conformations in which the membrane and cytoskeleton binding sites are masked. Thus, these proteins need to be conformationally activated to fulfill their functions.

A recent review has described in great detail the properties of ERM proteins and merlin, as well as their partners [6]. We thus focus this review on recent advances in understanding the mechanisms of activation of these proteins and on how these activated proteins transduce growth signals, with a special emphasis on tumor development.

Section snippets

Mechanisms of activation

ERM proteins are maintained in the closed conformation through the strong intramolecular N-/C-ERMAD interactions [6]. The crystal structure of the moesin N-ERMAD–C-ERMAD complex revealed that the C-ERMAD has an elongated structure that masks a large surface of the globular N-ERMAD domain [7••].

In cells, several stimuli are known to activate the ERM proteins. Thrombin activation of platelets induces membrane extensions containing moesin [8]. EGF stimulation of human carcinoma A431 cells induces

Signaling functions of ERM proteins and merlin

Activation of ERM proteins and their interaction with both the membrane and actin filaments controls cell morphogenesis, adhesion and motility, and also transduces growth signals for proliferation and survival.

A requirement for ERM proteins in the morphogenesis of specialized domains of the plasma membrane has been reported in several different systems. Ezrin, a protein found primarily in epithelial cells in vivo, is involved in the biogenesis of apical microvilli and in the formation of a

Merlin and ERM proteins in tumor development

The NF2 tumor suppressor gene displays bi-allelic inactivation in both sporadic and inherited schwannomas. Mouse models have been developed to study the NF2 syndrome experimentally. Homozygous knockout embryos died early during development [48], whereas heterozygous mice were viable but prone to develop a variety of tumors, mostly osteosarcomas [49]. To accurately model the human disease, a conditional knockout has been created using a Schwann cell specific promoter to drive the expression of

Conclusions

ERM proteins and merlin might represent two facets in the control of cell growth mediated by the organization of cortical actin. Merlin acts as a suppressor of cell growth whereas the role of ezrin in promoting cell growth and invasiveness is emerging. Recent studies have highlighted the importance of the conformational activation of these proteins in the transduction of growth signals. Both activating signals and downstream effectors of ERM proteins and merlin are being quickly identified and

Update

Recent papers report that ERM proteins colocalize with CD43 in a membrane domain distal to the immunological synapse 59., 60., 61.. Binding of ERM proteins to CD43 is required for exclusion of CD43 from the immunological synapse 59., 61.. Moreover, dominant-negative ezrin inhibits T cell activation 60., 61.. These results suggest that the relocalization of CD43, mediated by ERM proteins, is required for T cell activation.

Acknowledgements

We would like to thank J Plastino for comments on the manuscript. We apologize to colleagues whose original work was not cited due to space constraints. We acknowledge support from Association pour la Recherche contre le Cancer (ARC 5599) and la Ligue Nationale contre le Cancer.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (61)

  • P. Poullet et al.

    Ezrin interacts with focal adhesion kinase and induces its activation independently of cell matrix adhesion

    J Biol Chem

    (2001)
  • R.J. Shaw et al.

    Regulation of the neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli

    J Biol Chem

    (1998)
  • N. Akisawa et al.

    High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential

    Biochem Biophys Res Commun

    (1999)
  • K. Ohtani et al.

    Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of invasion of endometrial cancer cells

    Cancer Lett

    (1999)
  • K.D. Geiger et al.

    Ezrin immunoreactivity is associated with increasing malignancy of astrocytic tumors but is absent in oligodendrogliomas

    Am J Pathol

    (2000)
  • M. Tokunou et al.

    Altered expression of the ERM proteins in lung adenocarcinoma

    Lab Invest

    (2000)
  • F. Tort et al.

    Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma

    Lab Invest

    (2001)
  • J. Delon et al.

    Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin

    Immunity

    (2001)
  • A. Roumier et al.

    The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation

    Immunity

    (2001)
  • E.J. Allenspach et al.

    ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse

    Immunity

    (2001)
  • J.F. Gusella et al.

    Merlin: the neurofibromatosis 2 tumor suppressor

    Biochim Biophys Acta

    (1999)
  • M.F. James et al.

    The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association

    Biochem J

    (2001)
  • H.-M. Xu et al.

    Merlin differentially associates with the microtubule and actin cytoskeleton

    J Neurosci Res

    (1998)
  • E. Brault et al.

    Normal membrane localization and actin association of the NF2 tumor suppressor protein are dependent on foldings of its N-terminal domain

    J Cell Sci

    (2001)
  • A. Bretscher et al.

    ERM-merlin and EBP50 protein families in plasma membrane organization and function

    Annu Rev Cell Dev Biol

    (2000)
  • R.S. Shaw et al.

    RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane/actin protrusions in fibroblasts

    Mol Biol Cell

    (1998)
  • T. Matsui et al.

    Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinases

    Curr Biol

    (1999)
  • T. Matsui et al.

    Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association

    J Cell Biol

    (1998)
  • F. Nakamura et al.

    Regulation of F-actin binding to platelet moesin in vitro by both phosphorylation of threonine 558 and polyphosphatidylinositides

    Mol Biol Cell

    (1999)
  • A. Gautreau et al.

    Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane

    J Cell Biol

    (2000)
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