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Review
. 2022 Mar 17;23(6):3246.
doi: 10.3390/ijms23063246.

Pathophysiological Roles of Actin-Binding Scaffold Protein, Ezrin

Affiliations
Review

Pathophysiological Roles of Actin-Binding Scaffold Protein, Ezrin

Kotoku Kawaguchi et al. Int J Mol Sci. .

Abstract

Ezrin is one of the members of the ezrin/radixin/moesin (ERM) family of proteins. It was originally discovered as an actin-binding protein in the microvilli structure about forty years ago. Since then, it has been revealed as a key protein with functions in a variety of fields including cell migration, survival, and signal transduction, as well as functioning as a structural component. Ezrin acts as a cross-linker of membrane proteins or phospholipids in the plasma membrane and the actin cytoskeleton. It also functions as a platform for signaling molecules at the cell surface. Moreover, ezrin is regarded as an important target protein in cancer diagnosis and therapy because it is a key protein involved in cancer progression and metastasis, and its high expression is linked to poor survival in many cancers. Small molecule inhibitors of ezrin have been developed and investigated as candidate molecules that suppress cancer metastasis. Here, we wish to comprehensively review the roles of ezrin from the pathophysiological points of view.

Keywords: G protein; actin; cancer; ciliogenesis; cytoskeleton; ezrin; metastasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic structure of ERM proteins. ERM proteins are divided into three parts; that is, the N-terminal FERM domain (296 amino acid residues), the central α-helix structure, and the C-terminal F-actin binding domain shown in a blue box (90 amino acid residues). The FERM domain consists of three lobes (F1, F2, and F3) which form a compact clover-shaped structure. An asterisk in the C-terminal F-actin binding domain represents a functionally important Thr residue (Thr567) which is phosphorylated by several protein kinases. Amino acid numbers shown here are based on those of mouse ezrin. The overall structure is conserved in all ERM proteins.
Figure 2
Figure 2
The function of ezrin is strictly regulated by the interaction between the N- and C-terminal domains. The upper figure represents the inactive (or dormant) form of ezrin. In this form, the N-terminal FERM domain interacts with the C-terminal domain, which makes ezrin inactive and dormant. In the lower figure, the binding of PtdIns(4,5)P2 to the F3 lobe of the FERM domain (amino acid numbers 253, 254, 262, and 263 shown by an upward red arrow) and the subsequent phosphorylation of Thr567 residues (shown by a red asterisk) on the C-terminal domain by PKC, LOK, SLK, or ROCK (shown by a downward red arrow) open the inactive form into the active form. The activated ezrin is recruited to the apical membrane. These processes of activation seem to be common among the ERM proteins.
Figure 3
Figure 3
Ezrin functions as a cross-linker between membrane proteins and actin filaments directly or indirectly via scaffold proteins. (Left) Ezrin directly cross-links cell adhesion molecules such as CD44 and actin filaments. In this case, ezrin plays a key role in intermolecular communication between adhesion proteins attached to the extracellular matrix (ECM) and the actin cytoskeleton. (Right) Ezrin cross-links ion channels (such as CFTR), transporters (such as NHE3, Npt2a), and receptors (such as β2AR) to actin filaments indirectly via scaffold proteins such as NHERF1 (shown by orange boxes and circle). In this case, ezrin binds to the ERM binding site (shown by an orange circle) of scaffold proteins via the FERM domain (shown by clover-shaped green circles).
Figure 4
Figure 4
Ezrin functions as a regulator of plasma membrane tension. Plasma membrane tension is dominated by the attachment of actin filaments to the inner leaflet of the plasma membrane. Ezrin plays an important role by linking PtdIns(4,5)P2 (shown in red) located in the inner leaflet of the plasma membrane and the actin cytoskeleton. The membrane tension is increased by the increased amounts of PtdIns(4,5)P2 and by the activation of ezrin (shown in the upper part of figure). Conversely, it is decreased by the decreased amounts of PtdIns(4,5)P2 and by the inactivation of ezrin (shown in the lower part of figure).
Figure 5
Figure 5
Ezrin activates Rho GTPases. (a) RhoG (shown by blue circles) is activated by ezrin/PLEKHG6 interactions. PLEKHG6 is shown by three tandem red boxes. DH and PH represent Dbl homology domain and plekstrin homology domain, respectively. The N-terminal FERM domain of ezrin (shown by a green clover) binds to the C-terminal region (ezrin binding site) of PLEKHG6. The Ezrin-PLEKHG6 complex activates its effector, RhoG, and finally induces the formation of microvilli and membrane ruffles. (b) ARF6 (shown by an orange circle) is activated by ezrin/ACAP4 interactions. ACAP4 is shown by a red box. Ezrin is phosphorylated at Ser66 and interacts with ACAP4 phosphorylated at Thr545. The Ezrin/ACAP4 complex and activated ARF6 together induce membrane fusion of intracellular tubulovesicles with the apical membrane.
Figure 6
Figure 6
Ezrin is involved in several patterns of signal transduction. (a) In EGF signaling, ezrin cross-links the EGFR (shown by a couple of blue boxes) and actin filaments. In this process, ezrin itself is phosphorylated and activated by EGFR and other kinase(s) at Tyr145, Tyr353 and Thr567. (b) In HGF signaling, HGF binds its receptor tyrosine kinase, Met (shown by a couple of blue boxes), which phosphorylates a non-receptor tyrosine kinase, c-Src (shown by a yellow box). Ezrin is phosphorylated by c-Src at Tyr477, and interacts with Fes tyrosine kinase (shown by a green circle). Thus, Fes is indirectly cross-linked with the actin cytoskeleton, recruited at the sites of cell-cell contact, and functions in cell invasion and metastasis. (c) Ezrin cross-links the receptor of death ligand, CD95/Fas (shown by a blue box), and the actin cytoskeleton, which is followed by the association of FADD and caspase 8 to form the DISC complex for apoptosis. Rho (shown by a yellow circle) and ROCK (shown by a green box) also associate with the complex. (d) Ezrin binds to the regulatory subunit of PI3-kinase, p85 (shown by a red circle). PI3-kinase synthesizes PtdIns(3,4,5)P3, which activates its downstream target, protein kinase AKT, and protects against apoptosis.
Figure 7
Figure 7
Ezrin functions as an AKAP for the efficient phosphorylation of CFTR. The function of CFTR is regulated by phosphorylation of its regulatory domain (shown by a pink circle with a letter of R) by protein kinase A (PKA) (shown by a yellow circle with a letter of PK). Ezrin simultaneously binds to a regulatory subunit of PKA directly, and CFTR via a scaffold protein, NHERF1 (shown by orange boxes and circle). This CFTR-AKAP (ezrin)-PKA association on the membrane provides the necessary specificity for the phosphorylation-dependent regulation of the CFTR channel.
Figure 8
Figure 8
Ezrin functions as an F-actin binding protein for ciliogenesis. (a) In motile cilia, ezrin causes apical actin enrichment via interaction with actin filaments. Subsequently, the accumulation of BBs (shown by a black column) in the apical region promotes ciliary formation. Ezrin also interacts with ELMO (shown by a red box), which binds to DOCK1 (shown by an orange box). ELMO localizes along the axonemes and BBs in motile cilia. (b) When cells arrest in the G0 stage of the cell cycle, BB arises from the mother centriole (shown by a black column) of the centrosome, and forms the base of the primary cilium. In primary cilia, ELMO is localized at the mother centriole, whereas DOCK1 is localized to both mother and daughter centrioles.
Figure 9
Figure 9
Ezrin links the β2AR to actin filaments for stable expression of the receptor at the cell surface of airway ciliary cells. At the apical surface in motile ciliary cells, multiprotein complexes consisting of β2AR-NHERF1-ezrin links to the actin cytoskeleton to efficiently activate ciliary beating via the reception of procaterol.
Figure 10
Figure 10
The chemical structures of ezrin inhibitors, NSC305787, NSC668394, and MMV667492.

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