Ezrin Mediates Invasion and Metastasis in Tumorigenesis: A Review

Abstract

Ezrin, as encoded by the EZR gene, is a member of the Ezrin/Radixin/Moesin (ERM) family. The ERM family includes three highly related actin filament binding proteins, Ezrin, Radixin, and Moesin. These three members share similar structural properties containing an N-terminal domain named FERM, a central helical linker region, and a C-terminal domain that mediates the interaction with F-actin. Ezrin protein is highly regulated through the conformational change between a closed, inactivate form and an open, active form. As a membrane-cytoskeleton linker protein, Ezrin facilitates numerous signal transductions in tumorigenesis and mediates diverse essential functions through interactions with a variety of growth factor receptors and adhesion molecules. Emerging evidence has demonstrated that Ezrin is an oncogene protein, as high levels of Ezrin are associated with metastatic behavior in various types of cancer. The diverse functions attributed to Ezrin and the understanding of how Ezrin drives the deadly process of metastasis are complex and often controversial. Here by reviewing recent findings across a wide spectrum of cancer types we will highlight the structures, protein interactions and oncogenic roles of Ezrin as well as the emerging therapeutic agents targeting Ezrin. This review provides a comprehensive framework to guide future studies of Ezrin and other ERM proteins in basic and clinical studies.

Keywords: Ezrin; cancer; invasion; metastasis; migration.

FIGURE 1

Structure and activation process of Ezrin. Schematic representation of domain structure, activation states and binding partners of Ezrin protein. (A) Domain structure of Ezrin includes the N-terminal FERM domain (band 4.1 protein, Ezrin, Radixin, Moesin), the central α-helical linker region and the C-terminal ERM-associated domain (C-ERMAD, green). The FERM domain comprises three subdomains, F1, F2, and F3 (blue, red, and yellow) and C-ERMAD contains the F-actin-binding site. (B) The putative open state of Ezrin protein and its phosphorylation sites. (C) Various states and binding partners of Ezrin protein. (1) Ezrin is phosphorylated at several sites (e.g., T567 in Ezrin, T564 in Radixin and T558 in Moesin); (2) Ezrin is recruited to PIP2; (3) Activated Ezrin monomer (or head-to-tail dimer) binds with F-actin; (4) Ezrin binds with transmembrane receptors such as CD43/44, ICAM1/2 and NHE-1.

FIGURE 2

Ezrin change between normal cells and cancer cells. Physiological function and pathological effect of Ezrin protein in normal cells versus cancerous cells. Under physiological conditions, Ezrin proteins arrange the cytoskeleton of epithelial cells, mediate signaling pathways to generate an apical–basal polarity, normal cell morphology and consistent cell–cell contacts. Under pathological conditions, Ezrin proteins are upregulated and activated to promote cancer progression and metastasis in various types of epithelial cancers (breast, lung, and prostate). The relative membrane localization of Ezrin protein is increased, cell–cell contacts disrupted and therefore facilitates the process of cancer invasion.

FIGURE 3

Ezrin mediated signaling pathways and its pharmacological inhibitors.