Radixin: Roles in the Nervous System and Beyond

 FYI. Someone is stroke leadership needs to assign this to a brilliant researcher to figure out if this can be used for stroke recovery. But since there is NO leadership in stroke; NOTHING WILL OCCUR!

Radixin: Roles in the Nervous System and Beyond            

                                 by

Zhao Zhong Chong

^1,* and

Nizar Souayah

^1,2,*

¹

Department of Neurology, New Jersey Medical School, Rutgers University, 185 S. Orange Ave, Newark, NJ 07103, USA

²

Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA

^*

Authors to whom correspondence should be addressed.

Biomedicines 2024, 12(10), 2341; https://doi.org/10.3390/biomedicines12102341 (registering DOI)

Submission received: 16 September 2024 / Revised: 10 October 2024 / Accepted: 14 October 2024 / Published: 15 October 2024

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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Simple Summary

Radixin is a cytoskeletal-associated protein, a member of the ERM (ezrin, radixin, and moesin) protein family. Radixin plays important roles in cell shape, growth, and motility after activation by phosphorylation of its conserved threonine residues. Radixin functions as a relay in cell signaling pathways by binding to membrane proteins and transferring the cell signals into the cells. The pathogenic function of radixin has been found in central nervous system diseases, peripheral nerve injury, and cancers. We recently found significantly altered radixin in Schwann cells during elevated glucose, suggesting that it may be related to diabetes-induced nerve injury. As a result, the insight review into the roles of radixin and its associated cell signaling pathways may facilitate finding novel therapeutic targets for associated diseases.

Abstract

Background: Radixin is an ERM family protein that includes radixin, moesin, and ezrin. The importance of ERM family proteins has been attracting more attention, and studies on the roles of ERM in biological function and the pathogenesis of some diseases are accumulating. In particular, we have found that radixin is the most dramatically changed ERM protein in elevated glucose-treated Schwann cells. Method: We systemically review the literature on ERM, radixin in focus, and update the roles of radixin in regulating cell morphology, interaction, and cell signaling pathways. The potential of radixin as a therapeutic target in neurodegenerative diseases and cancer was also discussed. Results: Radixin research has focused on its cell functions, activation, and pathogenic roles in some diseases. Radixin and other ERM proteins maintain cell shape, growth, and motility. In the nervous system, radixin has been shown to prevent neurodegeration(This is good!) and axonal growth(Not clear; are we preventing or assisting axon growth?) . The activation of radixin is through phosphorylation of its conserved threonine residues. Radixin functions in cell signaling pathways by binding to membrane proteins and relaying the cell signals into the cells. Deficiency of radixin has been involved in the pathogenic process of diseases in the central nervous system and diabetic peripheral nerve injury. Moreover, radixin also plays a role in cell growth and drug resistance in multiple cancers. The trials of therapeutic potential through radixin modulation have been accumulating. However, the exact mechanisms underlying the roles of radixin are far from clarification. Conclusions: Radixin plays various roles in cells and is involved in developing neurodegenerative diseases and many types of cancers. Therefore, radixin may be considered a potential target for developing therapeutic strategies for its related diseases. Further elucidation of the function and the cell signaling pathways that are linked to radixin may open the avenue to finding novel therapeutic strategies for diseases in the nervous system and other body systems.

Keywords:

radixin; ERM; phosphorylation; neurodegeneration; peripheral nerve injury; cancer

1. Introduction

Radixin is one of the ERM family proteins, including ezrin, radixin, and moesin. ERM proteins, functioning as the link that bridges the actin cytoskeleton and membrane proteins, play very important roles in maintaining cell shape and motility through physically anchoring membrane proteins and assisting the signal transduction of post-translational processes [1]. ERMs also act as intracellular scaffolding proteins to relay the extracellular stimuli to the intracellular compartments of the cells [2]. In addition, ERMs have been demonstrated to regulate membrane dynamics and protrusion, cell adhesion, cell migration, and cell survival [2]. The broad cellular function of ERM implies that the deregulation of ERM holds potential roles in the development of diseases. In this article, we discussed the biological activity of ERM with a focus on radixin in a variety of diseases.

2. Activation of Radixin

2.1. Radixin Structure

The three ERM proteins possess similar structures, containing three major domains (Figure 1A,B). The amino terminus (N-terminus) is the four-point-one, ezrin, radixin, and moesin (FERM) domain that consists of F1, F2, and F3 subdomains (represented by A, B and C subdomains, respectively) [3]. The FERM domain, also named the N-terminal ERM-association domain (N-ERMAD), is the site for ERM proteins to interact with cell membranes. The FERM domain can bind to membranes, integral membrane proteins, and scaffolding proteins [4]. A central helical domain comprises three α helices, α1H, α2H, and α3H. α2H and α3H form a coiled-coil structure called the α-helical domain, while α1H acts as a linker region that connects the FERM domain and α-helical domain. The α-helical domain can bind to and mask the FERM domain. The carboxyl-terminal (C-terminal) end contains the F-actin binding domain, also known as the C-terminal ERM-association domain (C-ERMAD), which can bind the FERM domain and F-actin.

Figure 1. (A) Schematic ERM (ezrin, radixin, and moesin) protein domain structure. The N-terminus is the four-point-one, ezrin, radixin, moesin (FERM) domain that has F1, F2, and F3 subdomains. The FERM domain, also called N-terminal ERM association domain (N-ERMAD), is the site for ERM proteins to interact with the cell membrane. A central helical domain comprises three α helices, α1H, α2H, and α3H, which functions as a linker region connecting the FERM domain and an α-helical domain at the central portion of the protein. The α-helical domain can bind the FERM domain to facilitate the masking of both domains. The C-terminal end is the F-actin binding domain, also known as the C-terminal ERM-association domain (C-ERMAD), which has the ability to bind the FERM domain or F-actin. (B) The crystal structure of ERM proteins (reproduced from [3] and authorized by the publisher). (C) The inactive form of ERM proteins with C-ERMAD domain binding to and covering the FERM domain. (D) The active form of ERM proteins with the FERM domain released from the binding to the C-ERMAD domain.

2.2. Radixin Activation

While performing its biological activities, ERM changes its conformation from inactive to active. The two confirmations are inactive closed form and active open form. The FERM domain of ERM proteins is shut in an inactive state due to the interaction of the N-terminal end with the C-terminal regions [2]. As shown in Figure 1C, in the inactive closed conformation, the C-ERMAD domain binds and covers both the F-actin and N-ERMAD (FERM domain), masking interaction sites of the FERM domain and F domain, leading to the loss of their binding ability to the membrane proteins, cytoskeletal protein, and other adaptor proteins [5]. Further studies indicated that the central α-helix-rich domain and linker regions also interact with F1 and F2 of the FERM domain, contributing to the masking of the binding sites [6].

To release the FERM domain from intermolecular binding, phosphorylation of conserved residue, threonine (Thr), in the FERM domain is required. Thr phosphorylation disrupts the binding between the FERM domain and the C-ERMAD region, relieving the FERM domain from the intramolecular association (Figure 1D). The phosphorylation of radixin has been demonstrated to disrupt the binding to the N-terminal domain to recover the binding ability of FERM without affecting the F-actin binding site. Phosphorylation of ezrin and moesin simultaneously unmasks both the F-actin and FERM binding sites. Ezrin is activated through phosphorylation of Thr567 at the C-ERMAD domain [7], leading to attenuating the affinity of the FERM domain to the C-ERMAD and reopening the binding sites of F-actin. The equivalent phosphorylation sites of radixin and moesin are Thr564 and Thr558, respectively [8]. However, phosphorylation of C-terminal Thr573 of radixin is required for both F-actin binding and improves protein stability [9].

2.3. Kinases and Radixin Phosphorylation

Many cellular kinases can phosphorylate the residues in C-ERMAD domain (Table 1). G-protein coupled receptor kinase 2 (GRK2) phosphorylates ezrin on Thr567, and is involved in membrane protrusion and motility in epithelial cells [10] and in G protein-coupled receptor-dependent cytoskeletal reorganization [11]. GRK2 regulates cell migration during wound recovery in epithelial cell monolayers, at least partly by phosphorylating radixin [12]. Nick interacting kinase (NIK)-induced phosphorylation of ezrin on Thr567 is necessary for lamellipodium extension induced by growth factors [13]. Lymphocyte-oriented-kinase (LOK) is a major ERM kinase in resting lymphocytes, and phosphorylation of ezrin regulates the cytoskeletal organization of lymphocytes [14]. Protein kinase C (PKC) phosphorylates ezrin to regulate osteosarcoma cell migration [15]. PKC-alpha has been shown to prefer ezrin as its target for phosphorylation [16], while PKC-theta prefers to phosphorylate moesin on Thr558 [17]. However, phosphorylation of ezrin by PKC-iota is essential for its normal distribution, and may be involved in the differentiation of intestinal epithelial cells [18].

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