Spatial Control of Proton Pump H,K-ATPase Docking at the Apical Membrane by Phosphorylation-coupled Ezrin-Syntaxin 3 Interaction

Yu, Huijuan; Zhang, Jiajia; Takahashi, Hirohide; Yao, William; Suzuki, Yuki; Yuan, Xiao; Yoshimura, Shige H.; Zhang, Yin; Liu, Ya; Emmett, Nerimiah; Bond, Vincent C.; Wang, Dongmei; Ding, Xia; Yao, Xuebiao

doi:10.1074/jbc.m114.581280

Cited by 20 publications

(26 citation statements)

References 28 publications

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“…Using atomic force microscopic analyses, we show that phosphorylation of Ser-66 unfolds the three compact lobes of the FERM (protein 4.1, ezrin, radixin, moesin) domain and that this conformational change enables association of Stx3 with ezrin (13). Our study provides novel insights into the spatial control of H,K-ATPase docking by phosphorylation-coupled ezrin-Stx3 interaction in parietal cells.…”

mentioning

confidence: 96%

“…, and mCherry-ezrin S66D/T567D has been described previously (11)(12)(13). The infection efficiency and expression levels of various ezrin proteins exhibited no difference among different variants.…”

Section: Isolation Of Gastric Glands and Aminopyrine Uptake Assay-mentioning

confidence: 99%

“…4F). Previous studies have revealed that vacuole diameter can be used as a reporter for parietal cell secretory activity (13).…”

Section: T178dmentioning

confidence: 99%

“…To test whether MST4 is also involved in parietal cell activation, we carried out ezrin immunoprecipitation using ezrin antibodycoupled affinity beads incubated with cell lysates from cimetidine-treated parietal cells and histamine-treated samples (13). As shown in Fig.…”

Section: Dynamic Phosphorylation Of Ezrin During Parietalmentioning

confidence: 99%

“…The infection efficiency and expression levels of various ezrin proteins exhibited no difference among different variants. MST4 siRNA, whose targeted sequence was the same as described previously (13), was synthesized by Qiagen.…”

Section: Isolation Of Gastric Glands and Aminopyrine Uptake Assay-mentioning

confidence: 99%

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Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Jiang

Wang

Zhang

et al. 2015

Journal of Biological Chemistry

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Background: Polarized acid secretion in gastric parietal cells requires ezrin and its phosphorylation at Ser-66 by cAMP-dependent protein kinase (PKA). Results: Phosphorylation of Ser-66 induces an ezrin conformational change that promotes the phosphorylation of Thr-567 by MST4. Conclusion: PKA phosphorylates MST4 and ezrin to orchestrate histamine-elicited acid secretion. Significance: The PKA-MST4-ezrin signaling axis is essential for parietal cell activation.

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mentioning

confidence: 96%

Section: Isolation Of Gastric Glands and Aminopyrine Uptake Assay-mentioning

confidence: 99%

“…4F). Previous studies have revealed that vacuole diameter can be used as a reporter for parietal cell secretory activity (13).…”

Section: T178dmentioning

confidence: 99%

Section: Dynamic Phosphorylation Of Ezrin During Parietalmentioning

confidence: 99%

Section: Isolation Of Gastric Glands and Aminopyrine Uptake Assay-mentioning

confidence: 99%

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Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Jiang

Wang

Zhang

et al. 2015

Journal of Biological Chemistry

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Roles for H⁺/K⁺‐ATPase and zinc transporter 3 in cAMP‐mediated lysosomal acidification in bafilomycin A1‐treated astrocytes

Lee

Koh

2020

Glia

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Vacuolar ATPase (v‐ATPase) is the main proton pump that acidifies vesicles such as lysosomes. Disruption in the lysosomal localization of v‐ATPase leads to lysosomal dysfunction, thus contributing to the pathogenesis of lysosomal storage disorders and neurodegenerative diseases such as Alzheimer's disease. Recent studies showed that increases in cyclic AMP (cAMP) levels acidify lysosomes and consequently enhance autophagy flux. Although the upregulation of v‐ATPase function may be the key mechanism underlying the cAMP‐mediated lysosomal acidification, it is unknown whether a mechanism independent of v‐ATPase may be contributing to this phenomenon. In the present study, we modeled v‐ATPase dysfunction in brain cells by blocking lysosomal acidification in cortical astrocytes through treatment with bafilomycin A1, a selective v‐ATPase inhibitor. We observed that cAMP reversed the pH changes via the activation of protein kinase A; interestingly, cAMP also increased autophagy flux even in the presence of bafilomycin A1, suggesting the presence of an alternative route of proton entry. Notably, pharmacological inhibitors and siRNAs of H+/K+‐ATPase markedly shifted the lysosomal pH toward more alkaline values in bafilomycin A1/cAMP‐treated astrocytes, suggesting that H+/K+‐ATPase may be the alternative route of proton entry for lysosomal acidification. Furthermore, the cAMP‐mediated reversal of lysosomal pH was nullified in the absence of ZnT3 that interacts with H+/K+‐ATPase. Our results suggest that the H+/K+‐ATPase/ZnT3 complex is recruited to lysosomes in a cAMP‐dependent manner and functions as an alternative proton pump for lysosomes when the v‐ATPase function is downregulated, thus providing insight into the potential development of a new class of lysosome‐targeted therapeutics in neurodegenerative diseases.

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The Cell Biology of Gastric Acid Secretion

Okamoto¹,

Asano²,

Sakai³

2018

Physiology of the Gastrointestinal Tract

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Spatial Control of Proton Pump H,K-ATPase Docking at the Apical Membrane by Phosphorylation-coupled Ezrin-Syntaxin 3 Interaction

Cited by 20 publications

References 28 publications

Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Roles for H⁺/K⁺‐ATPase and zinc transporter 3 in cAMP‐mediated lysosomal acidification in bafilomycin A1‐treated astrocytes

The Cell Biology of Gastric Acid Secretion

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Spatial Control of Proton Pump H,K-ATPase Docking at the Apical Membrane by Phosphorylation-coupled Ezrin-Syntaxin 3 Interaction

Cited by 20 publications

References 28 publications

Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells

Roles for H+/K+‐ATPase and zinc transporter 3 in cAMP‐mediated lysosomal acidification in bafilomycin A1‐treated astrocytes

The Cell Biology of Gastric Acid Secretion

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Product

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Roles for H⁺/K⁺‐ATPase and zinc transporter 3 in cAMP‐mediated lysosomal acidification in bafilomycin A1‐treated astrocytes