ReviewERM proteins and NF2 tumor suppressor: the Yin and Yang of cortical actin organization and cell growth signaling
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
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2022, Seminars in Cell and Developmental BiologyCitation Excerpt :Furthermore, the active form of Moesin, the sole member of the ERM (Ezrin-Radixin-Moesin) family in Drosophila [68], localizes exclusively at the periphery of the BC cluster [69]. ERM proteins crosslink actin to the plasma membrane [70–72]. At the periphery of the cluster, Moesin and actin filaments form a supracellular structure, that surrounds the group of cells (Fig. 3 C).
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