Ezrin, Radixin and Moesin: key regulators of membrane-cortex interactions and signaling

Abstract

The cell cortex serves as a critical nexus between the extracellular environment/cell membrane and the underlying cytoskeleton and cytoplasm. In many cells, the cell cortex is organized and maintained by the Ezrin, Radixin and Moesin (ERM) proteins, which have the ability to interact with both the plasma membrane and filamentous actin. Although this membrane-cytoskeletal linkage function is critical to stability of the cell cortex, recent studies indicate that this is only a part of what ERMs do in many cells. In addition to their role in binding filamentous actin, ERMs regulate signaling pathways through their ability to bind transmembrane receptors and link them to downstream signaling components. In this review we discuss recent evidence in a variety of cells indicating that ERMs serve as scaffolds to facilitate efficient signal transduction on the cytoplasmic face of the plasma membrane.

Figure 1

ERM proteins are scaffolds for cAMP signaling pathways. A) A generic model of how ERMs act as A-kinase anchoring proteins (AKAPs). cAMP is produced following activation of GPCRs (in yellow, 7-pass transmembrane receptors), which in turn activate Adenylyl Cyclase (AC) to convert ATP to cAMP (yellow triangles). cAMP activates PKA, a heterotetramer, by binding to the regulatory (R) subunits, releasing the catalytic (C) subunits to phosphorylate nearby effector proteins. All three ERM proteins function as AKAPs, binding to the PKA regulatory subunits through their central alpha helical domain. ERM activation requires PIP₂ binding (red circles) and phosphorylation of a conserved residue within the FERM or F-actin binding domain (blue crescent). EBP50 (light blue), a scaffolding protein containing two PDZ domains and a FERM binding domain, binds to ERMs via a C-terminal domain and can interact with the G-protein coupled receptors (GPCRs) through its first PDZ domain [43]. B) At the immunological synapse Ezrin mediates T cell repression by functioning as an AKAP. Cbp, a transmembrane adaptor protein, binds to both EBP50 and Csk, a Src kinase. Ezrin can bind to EBP50 and scaffold PKA to Csk. Activated PKA phosphorylates Csk, which in turn phosphorylates Lck, a kinase and downstream component of T cell activation, at a residue that renders Lck inactive. This model was adapted from [44]. C) Radixin mediates TSH mediated proliferation by scaffolding the cAMP effectors PKA and Epac1 to their effector Rap1, a small GTPase. Epac1, a GEF for Rap1, is activated by binding of cAMP which releases Epac1 auto inhibition and activate Rap1 by catalyzing the exchange of GDP for GTP. Rap1 when activated localizes to the membrane. Activated PKA phosphorylates a residue that is crucial for Rap1’s ability to mediated TSH proliferation. Although schematized here, EBP50 has not been shown to function in this pathway. D) Ezrin’s scaffolding function is required for gastric acid secretion. In parietal cells Ezrin is phosphorylated within the FERM domain by PKA, which is activated in part through activated histamine receptors. Phosphorylated Ezrin is a scaffold for ACAP4, an ARF6 GAP. ARF6 regulates membrane trafficking and requires the ability to cycle between active (GTP-bound) and inactive (GDP-bound) states for its function. Ezrin, ACAP4 and cycling ARF6 are all necessary for proper localization of the H⁺,K⁺-ATPase for gastric acid secretion. Although indicated here, EBP50 has not been shown to function in this pathway, nor has Ezrin been shown to scaffold PKA in parietal cells.