Nephrin–Ephrin-B1–Na+/H+ Exchanger Regulatory Factor 2–Ezrin–Actin Axis Is Critical in Podocyte Injury

Fukusumi, Yoshiyasu; Yasuda, Hidenori; Zhang, Ying; Kawachi, Hiroshi

doi:10.1016/j.ajpath.2021.04.004

Cited by 3 publications

(5 citation statements)

References 62 publications

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“…However, some changes in these proteins were evident in SLK KO GECs and mice, particularly in the context of adriamycin. A recent study has proposed ezrin linking F‐actin with ephrin B1, and ephrin B1 interacting with nephrin (Fukusumi et al., 2021 ). This pathway involving ezrin could potentially be regulated by SLK.…”

Section: Discussionmentioning

confidence: 99%

Role of the Ste20‐like kinase SLK in podocyte adhesion

Cybulsky,

Papillon,

Bryan

et al. 2024

Physiological Reports

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SLK controls the cytoskeleton, cell adhesion, and migration. Podocyte‐specific deletion of SLK in mice leads to podocyte injury as mice age and exacerbates injury in experimental focal segment glomerulosclerosis (FSGS; adriamycin nephrosis). We hypothesized that adhesion proteins may be substrates of SLK. In adriamycin nephrosis, podocyte ultrastructural injury was exaggerated by SLK deletion. Analysis of a protein kinase phosphorylation site dataset showed that podocyte adhesion proteins—paxillin, vinculin, and talin‐1 may be potential SLK substrates. In cultured podocytes, deletion of SLK increased adhesion to collagen. Analysis of paxillin, vinculin, and talin‐1 showed that SLK deletion reduced focal adhesion complexes (FACs) containing these proteins mainly in adriamycin‐induced injury; there was no change in FAC turnover (focal adhesion kinase Y397 phosphorylation). In podocytes, paxillin S250 showed basal phosphorylation that was slightly enhanced by SLK; however, SLK did not phosphorylate talin‐1. In adriamycin nephrosis, SLK deletion did not alter glomerular expression/localization of talin‐1 and vinculin, but increased focal adhesion kinase phosphorylation modestly. Therefore, SLK decreases podocyte adhesion, but FAC proteins in podocytes are not major substrates of SLK in health and disease.

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Section: Discussionmentioning

confidence: 99%

Role of the Ste20‐like kinase SLK in podocyte adhesion

Cybulsky,

Papillon,

Bryan

et al. 2024

Physiological Reports

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“…We observed that phosphorylation of ezrin was increased in glomeruli of rCrb2-immunized mice in vivo and in Crb2-expressing immortalized mouse podocytes exposed to anti-Crb2 antibody in vitro . Because the intracellular domain of Crb2 is known to interact with ezrin, a known linker of the membrane protein and the actin cytoskeleton, 29 , 30 it is plausible that Crb2 antibodies activate phosphorylation of ezrin by crosslinking and aggregating Crb2. Indeed, Crb family proteins are believed to form homophilic binding 49 and our results support the capacity of Crb2 to oligomerize (Supplemental Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…22 The phosphorylated ERM proteins act as a critical linker between the plasma membrane and the actin cytoskeleton. 29,30 Thus, Crb2 could work as a signaling molecule and regulate the actin cytoskeleton in podocytes via ERM proteins and/or nephrin. Conversely, altered Crb2 signaling pathways may result in actin derangement and FP effacement.…”

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confidence: 99%

“…The short cytoplasmic domain of Crb2 has binding motifs to the ERM (ezrin/radixin/moesin) and the PDZ (PSD-95/Discs large/ZO-1) family proteins and a tyrosine residue 22 . The phosphorylated ERM proteins act as a critical linker between the plasma membrane and the actin cytoskeleton 29 , 30 . Thus, Crb2 could work as a signaling molecule and regulate the actin cytoskeleton in podocytes via ERM proteins and/or nephrin.…”

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confidence: 99%

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A Novel Mouse Model of Idiopathic Nephrotic Syndrome Induced by Immunization with the Podocyte Protein Crb2

Hada

Shimizu

Takematsu

et al. 2022

JASN

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Background: The cause of podocyte injury in idiopathic nephrotic syndrome (INS) remains unknown. Although recent evidence points to the role of B cells and autoimmunity, the lack of animal models mediated by autoimmunity limits further research. We aimed to establish a mouse model mimicking human INS by immunizing mice with Crb2, a transmembrane protein expressed at the podocyte foot process. Methods: C3H/HeN mice were immunized with the recombinant extracellular domain of mouse Crb2. Serum anti-Crb2 antibody, urine protein-to-creatinine ratio, and kidney histology were studied. For signaling studies, a Crb2-expressing mouse podocyte line was incubated with anti-Crb2 antibody. Results: Serum anti-Crb2 autoantibodies and significant proteinuria were detected 4 weeks after the first immunization. The proteinuria reached nephrotic range at 9-13 weeks and persisted up to 29 weeks. Initial kidney histology resembled minimal change disease in humans, and immunofluorescence staining showed delicate punctate IgG staining in the glomerulus, which co-localized with Crb2 at the podocyte foot process. A subset of mice developed features resembling focal segmental glomerulosclerosis after 18 weeks. In glomeruli of immunized mice as well as in Crb2-expressing podocytes incubated with anti-Crb2 antibody, phosphorylation of ezrin, which connects Crb2 to the cytoskeleton, increased, accompanied by altered Crb2 localization and actin distribution. Conclusion: The results highlight the causative role of anti-Crb2 autoantibody in podocyte injury in mice. Crb2 immunization could be a useful model to study the immunological pathogenesis of human INS, and may support the role of autoimmunity against podocyte proteins in INS.

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“…In glomerular podocytes, Ezrin has also been reported to form a multi-protein complex with NHERF2 and podocalyxin [ 179 ], and the loss of Ezrin reduced susceptibility to glomerular injury in mice [ 180 ]. A recent study found that this protein complex also interacts with nephrin and ephrin-B1, forming an axis critical to podocyte injury [ 181 ].…”

Section: Ezrin Interacts With Metastasis-related Proteinsmentioning

confidence: 99%

Ez-Metastasizing: The Crucial Roles of Ezrin in Metastasis

Buenaventura,

Merlino,

2023

Cells

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Ezrin is the cytoskeletal organizer and functions in the modulation of membrane–cytoskeleton interaction, maintenance of cell shape and structure, and regulation of cell–cell adhesion and movement, as well as cell survival. Ezrin plays a critical role in regulating tumor metastasis through interaction with other binding proteins. Notably, Ezrin has been reported to interact with immune cells, allowing tumor cells to escape immune attack in metastasis. Here, we review the main functions of Ezrin, the mechanisms through which it acts, its role in tumor metastasis, and its potential as a therapeutic target.

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Nephrin–Ephrin-B1–Na+/H+ Exchanger Regulatory Factor 2–Ezrin–Actin Axis Is Critical in Podocyte Injury

Cited by 3 publications

References 62 publications

Role of the Ste20‐like kinase SLK in podocyte adhesion

Role of the Ste20‐like kinase SLK in podocyte adhesion

A Novel Mouse Model of Idiopathic Nephrotic Syndrome Induced by Immunization with the Podocyte Protein Crb2

Ez-Metastasizing: The Crucial Roles of Ezrin in Metastasis

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