Trends in Cell Biology
ReviewMerlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortex
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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