Merlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortex

doi:10.1016/j.tcb.2009.02.006

Trends in Cell Biology

Volume 19, Issue 5, May 2009, Pages 198-206

https://doi.org/10.1016/j.tcb.2009.02.006 Get rights and content

Recent studies highlight the importance of the distribution of membrane receptors in controlling receptor output and in contributing to complex biological processes. The cortical cytoskeleton is known to affect membrane protein distribution but the molecular basis of this is largely unknown. Here, we discuss the functions of Merlin and the ERM proteins both in linking membrane proteins to the underlying cortical cytoskeleton and in controlling the distribution of and signaling from membrane receptors. We also propose a model that could account for the intricacies of Merlin function across model organisms.

Introduction

Increasing evidence indicates that the distribution and aggregation of receptors across the plasma membrane is exquisitely choreographed, particularly in the highly organized tissues of multicellular organisms. External physical cues such as contact with an adjacent cell or basement membrane can clearly affect the positioning of various adhesion receptors within the membrane; however, it is now appreciated that signaling from many types of receptors can also be regulated intrinsically at the level of the distribution of receptors across the membrane. This distribution is primarily governed by protein- and/or lipid-mediated complex assembly, which, in turn, can affect receptor trafficking and signaling. The interface between the membrane and the underlying cortical cytoskeleton has an active and dynamic role in this choreography.

Local changes in membrane–cytoskeleton interaction can affect membrane protein complexes and cortical cytoskeleton organization, contributing to the establishment and maintenance of architecturally and functionally distinct membrane compartments. Proteins such as ankyrin, spectrin, filamin and myristoylated alanine-rich C kinase substrate (MARCKS) have a key role in this process 1, 2, 3. In addition, multiple lines of evidence indicate that proteins containing Four point one, Ezrin, Radixin, Moesin (FERM) domains are important mediators of dynamic membrane–cytoskeleton adhesion (Box 1). Here, we consider recent evidence that the FERM-domain-containing neurofibromatosis type 2 (NF2) tumor suppressor, known as Merlin, and the closely related Ezrin, Radixin and Moesin (ERM) proteins, function both to stabilize the membrane–cytoskeleton interface and to organize the distribution of, and signaling by, membrane receptors. First, we consider how the distribution of membrane receptors is controlled at the membrane–cytoskeleton interface and then describe the role of FERM-domain proteins, and Merlin and ERM (Merlin/ERM) proteins specifically, in regulating receptor distribution and function in different model organisms. We ultimately propose a unified model to explain the available data and complex biological consequences attributed to Merlin/ERM function across species.

Section snippets

Plasma membrane organization

The cortical cytoskeleton provides both tensile architectural support for cellular appendages such as microvilli and a scaffold for membrane protein complexes that partition the membrane–cytoskeleton interface into physically and functionally distinct domains. Several factors affect the assembly of specialized membrane protein complexes which, in turn, contribute to the formation of larger scale membrane appendages. For example, extracellular cues effect local changes in the delivery and

FERM-domain-containing proteins integrate multiple signals at the cell cortex

Studies of the mature erythrocyte cytoskeleton provide both a historical foundation and a useful model for considering the interface between membrane receptors and the cortical cytoskeleton [2]. The red blood cell membrane adheres tightly to the underlying spectrin–actin cytoskeleton through direct association of spectrin with membrane lipids and through the membrane–cytoskeleton linking proteins ankyrin and Protein 4.1, which interact with membrane receptors. This tight linkage is associated

Merlin/ERM-mediated membrane–cytoskeleton attachment

In an ‘open’, active conformation, the ERM C-terminal domain can directly bind to actin filaments. Local activation of the membrane–cytoskeleton linking activity of the ERM proteins is important during bleb retraction and drives crucial changes in cortical stiffness and spindle positioning that are necessary for successful progression through spindle assembly checkpoints during mitosis 25, 26, 27. Defects in ERM-mediated membrane–cytoskeleton attachment and cortical tension have been proposed

ERM-controlled membrane-receptor complexes

In addition to stabilizing the membrane–cytoskeleton interface, an increasing number of studies now recognize that the ERM proteins also, probably simultaneously, affect the distribution and function of receptors at the plasma membrane. Here, we describe three examples that highlight the variety of ways in which the ERM proteins impact the distribution of membrane receptors. In each case, the control of individual membrane receptor complexes probably contributes to larger-scale membrane

Merlin regulates receptor surface abundance and signaling

Despite extensive analyses of Merlin function over the past 15 years, its role in tumor suppression remains obscure. However, recent studies in flies and in mice indicate that Merlin controls proliferation by regulating growth-factor-receptor abundance and/or availability at the cell surface (Figure 2a). In Drosophila, this function is redundant with another FERM-domain-containing tumor suppressor, Expanded 12, 52. In cells lacking both Merlin and Expanded, growth-factor receptors including the

Signaling and biological output

A key unmet challenge is to delineate the complexity of Merlin/ERM-containing membrane complexes in a given cell or tissue. Does the FERM domain simultaneously associate with multiple membrane proteins? Do Merlin/ERM proteins assemble multiple different complexes within the same cell? Competition between membrane targets could provide the basis for how Merlin/ERM proteins nucleate distinct complexes within the same cell. Indeed, structural studies suggest that the interaction of the radixin

Concluding remarks and future perspectives

Future studies that probe the molecular basis of how Merlin/ERM proteins regulate receptor abundance and localization are likely to advance our understanding of Merlin/ERM-dependent changes in membrane-receptor distribution and more broadly of the mechanisms cells use to control receptor localization and activity in flies and mammals. This has important implications not only for understanding how cells normally orchestrate receptor distribution and function during development and in adult

Acknowledgements

The authors would like to thank the members of the McClatchey and Fehon laboratories for helpful comments and discussions. This work was supported by NIH RO1 CA113733 and DOD W81XWH-05-1-0189 to A.I.M. and NIH RO1 NS034738 to R.G.F.

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The NF2-encoded protein, merlin, links plasma membrane receptors to the actin cytoskeleton and modulates signaling pathways related to cell morphology, proliferation, and survival.3 Its interactions with different signaling pathways are multiple and complex, involving mTORC1/mTORC2,4–7 receptor tyrosine kinases,8 Rac/p21-activated kinase,9,10 Hippo signaling,11,12 and a nuclear function regulating the E3 ubiquitin ligase, CRL4DCAF1.13 Merlin interacts with at least 38 other proteins in different contexts.14–18
Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2.
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Trends in Cell Biology

ReviewMerlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortex

Introduction

Section snippets

Plasma membrane organization

FERM-domain-containing proteins integrate multiple signals at the cell cortex

Merlin/ERM-mediated membrane–cytoskeleton attachment

ERM-controlled membrane-receptor complexes

Merlin regulates receptor surface abundance and signaling

Signaling and biological output

Concluding remarks and future perspectives

Acknowledgements

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

Dev. Cell

Pak1. Mol. Cell

Curr. Biol.

J. Biol. Chem.

Cell

J. Mol. Biol.

Structure

J. Biol. Chem.

Curr. Biol.

Dev. Cell

Dev. Biol.

Dev. Cell

J. Biol. Chem.

Cell

Blood

Semin. Immunol.

Immunity

Curr. Opin. Cell Biol.

Dev. Cell

Cell

Semin. Cancer Biol.

Semin. Hematol.

J. Biol. Chem.

Lancet Neurol.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Eur. J. Cell Biol.

Exp. Cell Res.

Eur. J. Cell Biol.

J. Biol. Chem.

FEBS Lett.

Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues

Physiol. Rev.

Continuous membrane-cytoskeleton adhesion requires continuous accommodation to lipid and cytoskeleton dynamics

Annu. Rev. Biophys. Biomol. Struct.

Cell control by membrane-cytoskeleton adhesion

Nat. Rev. Mol. Cell Biol.

Harnessing actin dynamics for clathrin-mediated endocytosis

Nat. Rev. Mol. Cell Biol.

Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules

Annu. Rev. Biophys. Biomol. Struct.

ERM proteins and merlin: integrators at the cell cortex

Nat. Rev. Mol. Cell Biol.

Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity

Nature

Contact-dependent inhibition of EGFR signaling by Nf2/Merlin

J. Cell Biol.

The structure of the FERM domain of merlin, the neurofibromatosis type 2 gene product

Acta Crystallogr. D Biol. Crystallogr.

The association of NHERF adaptor proteins with g protein-coupled receptors and receptor tyrosine kinases

Annu. Rev. Physiol.

Expression level, subcellular distribution and rho-GDI binding affinity of merlin in comparison with Ezrin/Radixin/Moesin proteins

Oncogene

Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl

Oncogene

Review
Merlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortex