Phosphorylated T567 ezrin is associated with merlin expression in KIT-mutant gastrointestinal stromal tumors

Weng, Wen‐Hui; Yeh, Chun‐Nan; Cheng, Yung-Feng; Lenka, Govinda; Liaw, Yi-Wei

doi:10.3892/mmr.2011.609

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…Interestingly, Zawawi et al[ 45 ] previously reported that the blockade of moesin function inhibited the LPS-induced activation of MyD88, IRAK and TRAF6, as well as subsequent MAPK activation and NF-κB translocation to the nucleus. Weng et al [ 47 ] also confirmed that the phosphorylation of ezrin triggered MAPK signal transduction in tumor progression. Thus, our results are consistent with a specific role for the ERM family in the activation of p38 and NF-κB activation.…”

Section: Discussionmentioning

confidence: 88%

The ROCK-ezrin signaling pathway mediates LPS-induced cytokine production in pulmonary alveolar epithelial cells

Ding

et al. 2022

Cell Commun Signal

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Background Ezrin/radixin/moesin (ERM) proteins are members of the protein 4.1 superfamily and function as linkers that connect the actin cytoskeleton to the plasma membrane of cells. ERM also play critical role in the Lipopolysaccharide (LPS)-induced inflammatory response. However, the signaling mechanisms involved in this process remain unclear. In this study, we aimed to investigate the potential role of the rho-associated coiled-coil containing protein kinase (ROCK) pathway in LPS-induced ezrin phosphorylation and cytokine production in pulmonary alveolar epithelial cells. Methods Cultured A549 and HPAEpiC cells were treated with LPS. The expression and localization of ezrin in A549 and HPAEpiC cells were then analyzed by western blotting and immunoflurescence. Activation of RhoA/ROCK was assessed by western blotting and RhoA activity assays. The interaction of ezrin with Syk and myeloid differentiation factor 88 (MyD88)/IL-1R-associated kinase 1 (IRAK-1) was investigated by co-immunoprecipitation. The activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) was measured with electrophoretic mobility shift assays and by western blotting. ELISA and western blotting were performed to detect the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and high mobility group box 1 protein (HMGB1) release into the culture supernatant, and cellular HMGB1 levels. Results LPS induced ezrin phosphorylation in a concentration- and time-dependent manner. The blockade of RhoA/ROCK inhibited LPS-induced ezrin phosphorylation and its translocation from the cytoplasm to the cell membrane. Co-immunoprecipitation assays further revealed that ezrin associated with Syk constitutively, but only associated with MyD88/IRAK-1 upon LPS challenge. Moreover, LPS-induced p38 and nuclear NF-κB activation was found to be ezrin dependent. The suppression of ezrin by siRNA or the blockade of ROCK activation with Y-27632 reduced the production of TNF-α, IL-1β, and HMGB1 in response to LPS. Conclusions Our findings reveal a novel regulatory mechanism involving ezrin in the LPS-induced production of pro-inflammatory cytokines, and highlight the importance of the RhoA/ROCK-ezrin/Syk-MyD88/IRAK1 axis. Data presented in this manuscript provide novel insights into the signaling pathways activated in pulmonary alveolar epithelial cells by LPS.

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Section: Discussionmentioning

confidence: 88%

The ROCK-ezrin signaling pathway mediates LPS-induced cytokine production in pulmonary alveolar epithelial cells

Ding

et al. 2022

Cell Commun Signal

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“…Interestingly, Zawawi et al [16] previously reported that the blockade of moesin function inhibited the LPS-induced activation of MyD88, IRAK and TRAF6, as well as subsequent MAPK activation and NF-κB translocation to the nucleus. Weng et al [37] also con rmed that the phosphorylation of ezrin triggered MAPK signal transduction in tumor progression. Thus, our results are consistent with a speci c role for the ERMs family in the activation of p38 and NF-κB activation.…”

Section: Discussionmentioning

confidence: 93%

The ROCK-Ezrin Signaling Pathway Mediates LPS-Induced Cytokine Production in A549 Cells

Ding

Gao

et al. 2021

Preprint

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Background: Ezrin/radixin/moesin proteins (ERMs) are members of the protein 4.1 superfamily and function as linkers that connect the actin cytoskeleton to the plasma membrane of cells. ERMs also play critical role in the Lipopolysaccharide (LPS)-induced inflammatory response. However, the signaling mechanisms involved remain unclear. This study aims to investigate the potential role of the rho-associated coiled-coil containing protein kinase (ROCK) pathway in LPS-induced ezrin phosphorylation and cytokine production in A549 cells. Methods: Cultured A549 cells were treated with LPS. The expression and localization of ezrin in A549 cells were analyzed by Western bloting and immunoflurescence. The activation of RhoA/ROCK was assessed by Western bloting and RhoA activity assays. The interaction of ezrin with Syk and myeloid differentiation factor 88 (MyD88)/IL-1R-associated kinase 1 (IRAK-1) was investigated using co-immunoprecipitation. The activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) was measured with electrophoretic mobility shift assay and Western blotting. ELISA and Western bloting were performed to detect tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and high mobility group box 1 protein (HMGB1) release into the culture supernatant and cellular HMGB1 levels.Results: Here, we show that LPS induced ezrin phosphorylation in a concentration- and time-dependent manner. The blockade of RhoA/ROCK inhibited LPS-induced ezrin phosphorylation and its translocation from the cytoplasm to the cell membrane. Co-immunoprecipitation assays further revealed that ezrin associated with Syk constitutively, but only associated with MyD88/IRAK-1 upon LPS challenge. Moreover, LPS-induced p38 and nuclear NF-κB activation was found to be ezrin dependent. The suppression of ezrin by siRNA or the blockade of ROCK activation with Y-27632 reduced the production of TNF-α, IL-1β, and HMGB1 in response to LPS. Conclusions: Our findings reveal a novel regulatory mechanism involving ezrin in LPS induced the production of pro-inflammatory cytokines, and highlight the importance of the RhoA/ROCK-MyD88/IRAK1-ezrin/Syk axis. Data presented in this manuscript provide novel insights into the signaling pathways activated in A549 cells by LPS.

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“…Inhibiting ezrin function in these transformed cells abolishes fos-mediated membrane ruffling and cell motility [7]. Furthermore, GIST harbors a mutation in the KIT oncogene that activates ezrin at different residues to promote tumor progression [111]. …”

Section: Ezrin Activation and Role In Biologymentioning

confidence: 99%

Sphingolipid regulation of ezrin, radixin, and moesin proteins family: Implications for cell dynamics

Adada

Canals

Hannun

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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A key but poorly studied domain of sphingolipid functions encompasses endocytosis, exocytosis, cellular trafficking, and cell movement. Recently, the ezrin, radixin and moesin (ERM) family of proteins emerged as novel potent targets regulated by sphingolipids. ERMs are structural proteins linking the actin cytoskeleton to the plasma membrane, also forming a scaffold for signaling pathways that are used for cell proliferation, migration, and invasion, and cell division. Opposing functions of the bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P), contribute to ERM regulation. S1P robustly activates whereas ceramide potently deactivates ERM via phosphorylation/dephosphorylation, respectively. This recent dimension of cytoskeletal regulation by sphingolipids opens up new avenues to target cell dynamics, and provides further understanding of some of the unexplained biological effects mediated by sphingolipids. In addition, these studies are providing novel inroads into defining basic mechanisms of regulation and action of bioactive sphingolipids. This review describes the current understanding of sphingolipid regulation of the cytoskeleton, it also describes the biologies in which ERM proteins have been involved, and finally how these two large fields have started to converge.

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Phosphorylated T567 ezrin is associated with merlin expression in KIT-mutant gastrointestinal stromal tumors

Cited by 3 publications

References 41 publications

The ROCK-ezrin signaling pathway mediates LPS-induced cytokine production in pulmonary alveolar epithelial cells

The ROCK-ezrin signaling pathway mediates LPS-induced cytokine production in pulmonary alveolar epithelial cells

The ROCK-Ezrin Signaling Pathway Mediates LPS-Induced Cytokine Production in A549 Cells

Sphingolipid regulation of ezrin, radixin, and moesin proteins family: Implications for cell dynamics

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