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

Abstract

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.

Figure 1

Merlin/ERM proteins organize membrane receptor complexes and membrane domains. (a) Merlin/ERM proteins can assemble multiprotein complexes containing membrane receptors, adapters and Rho GTPase regulators or effectors and link them to the cortical cytoskeleton. Merlin/ERM proteins can interact directly with the positively charged juxtamembrane region of certain membrane receptors; alternatively, Merlin/ERM proteins can associate with the tandem PDZ-domain-containing adapter NHERF-1, which, in turn, can directly associate with several receptors including multipass receptors such as NHE3 or CFTR and single-pass receptors such as EGFR or PDGFR. Larger multiprotein membrane complexes could be assembled via homo-, hetero- or oligo-merization of Merlin/ERMs and/or NHERF proteins. The presence of unique lipid environments, to which specific proteins localize, might cooperate to establish unique membrane receptor complexes containing Merlin/ERM proteins. (b) The ERM proteins (green) are particularly important for strengthening the membrane–cortical-cytoskeleton interface and controlling the surface availability of certain membrane receptors at the apical membrane. In addition, fly Moesin stabilizes cortical actin at the apical junctional region through association with Bitesize. By contrast, Merlin (red) function is important for establishing stable adherens junctions, perhaps by stabilizing the interface between the junction and cortical cytoskeleton. Merlin can also control the surface availability of certain receptors, particularly in the apical junctional region.

Figure 2

Models of Merlin-dependent membrane receptor distribution in flies and mammalian cells. Studies in flies and mammals both conclude that Merlin can control the surface abundance or distribution of EGFR (and other receptors in flies), but they seem to reach differing conclusions as to the proximal effect of Merlin on EGFR. (a) In flies, loss of Merlin and the related tumor suppressor Expanded yield increased surface abundance of and signaling from EGFR, suggesting that Merlin might normally promote receptor clearance (endocytosis and degradation) or inhibit receptor recycling. (b) In mammalian cells, loss of Merlin yields persistent EGFR internalization and signaling at high cell density, which does not occur in confluent wild-type cells, indicating that Merlin normally prevents EGFR endocytosis and signaling upon cell:cell contact. NHERF-1 is required for Merlin–EGFR interaction in mammalian cells. Merlin also complexes with both EGFR and E-cadherin upon cell:cell contact, which could facilitate the establishment of stable adherens junctions. We believe that the apparently contradictory conclusions of the fly and mammalian studies can be reconciled through the model shown in Figure 2c. This model posits that the primary function of Merlin is to direct EGFR to a specific membrane compartment from which it is poised to use a particular endocytic pathway.