Radixin: Roles in the Nervous System and Beyond

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 neurodegeneration and axonal 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: ERM; cancer; neurodegeneration; peripheral nerve injury; phosphorylation; radixin.

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.

Figure 2

Radixin-induced cell signaling pathways. Radixin can bind directly to the cytoplasmic tails of many membrane proteins, including CD44, CD43, CD95, intracellular adhesion molecule 1-3 (ICAM 1-3), L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), integrin alpha M/beta2, calcium-binding EF-hand-like S100 protein, regulating cell shape, migration, and other cell interacting processes. Radixin can also interact with proteins through the adaptor protein ERM-binding phosphoprotein 50 (EBP50) and NHE3 kinase A regulatory protein (E3KARP). Na⁺/H⁺ exchange regulatory cofactor (NHERF3) can bind to EBP50 and undergo a conformational change. Patched protein (PTCH), a Hedgehog receptor, can bind to EBP50 or directly to radixin. The binding of Hedgehog to PTCH induces zinc finger-domain-bearing protein (ZFBP) and subsequent expression of its target genes. Neuron-associated developmentally regulated protein (NADRIN) interacts with EBP50, leading to its inactivation of and morphological differentiation of astrocytes. Radixin can regulate Galpha13 (G13)-mediated signaling pathways. Radixin mediates serum response element (SRE)-dependent gene transcription through activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and calmodulin-dependent protein kinase (CaMKII). Radixin-mediated Rac1 can also regulate cell shape, migration, and cell–cell adhesion. Radixin may be involved in the lipopolysaccharide-Notinduced release of proinflammatory cytokines through nuclear factor (NF)-κB by recruiting interleukin-1 receptor-associated kinases (IRAKs)/myeloid differentiation primary response 88 (MYD88) followed by activation of NF-κB, leading to an increase in gene expression of inflammatory cytokines.

Figure 3

The roles of radixin in the nervous system. Radixin promotes neural progenitor cell migration and neuroblast proliferation in the subventricular zone (SVZ) and the rostral migratory stream, possibly promoting functional recovery after brain injury. Radixin also plays a role in neurite formation and the development of neuronal polarity via regulating growth cone development and maintenance. Radixin is expressed in stereocilia of the inner ear sensory cells and is necessary for the conversion of sound into electrical signals at an acoustic rate. Moreover, radixin is necessary for γ-Aminobutyric acid type A (GABAA) receptor alpha5 subunit (GABAAR-α5) to anchor at the actin cytoskeleton to mediate tonic inhibition and hippocampal-dependent short-term memory. Furthermore, radixin has been shown to function to maintain the plasma membrane localization and transport activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and glucose transporter 1 (GLUT1) proteins through the blood–brain barrier (BBB) illustrated in an in vitro model, which may facilitate the access of therapeutic drugs into the brain. Accordingly, targeting radixin has the potential for the treatment of stroke, neurodegenerative diseases, and hearing loss.

Figure 4

The spectral counting ratio of radixin in Schwann cells after elevated glucose treatment. The Human Schwann cell line was cultured at 37 °C in a humidified atmosphere (5%C02/95% air) in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum. When cells were at 50–70% confluence, the culture medium was changed with either low (GL, 5.5 mM) or high (GH, 33 mM) glucose, and the cell culture continued. Then, the cell protein extracts were prepared after the cultures had been maintained under low or high glucose for 72 h. The samples of cells were fully separated on SDS-PAGE and divided into two groups (high abundant protein gel band and low abundant protein gel band). The resulting 4-peptide samples were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) on Orbitrap Velos MS instrument. The MS/MS spectra were searched against a Swissport human database using a local MASCOT search engine (V.2.3). The relative protein abundance was calculated based on spectrum counting. The significance (p < 0.05) of the ratio was achieved by t-test between the low and high glucose groups, n = 3. RADI: radixin.