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
复制标题
细胞极性激酶 MST4 与 cAMP 依赖性激酶配合协调胃壁细胞中组胺刺激的酸分泌。
DOI：
10.1074/jbc.m115.668855
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发表时间：
2015-11-20
影响因子：
4.8
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Jiang, Hao;Wang, Wenwen;Yao, Xuebiao
胃的消化功能取决于胃腔的酸化。胃酸分泌到管腔是由PKA级联激活触发的，最终导致胃H，K-ATPase插入壁细胞顶端质膜。Ezrin是一种偶联蛋白，其在Ser-66处被PKA磷酸化是壁细胞激活所必需的。然而，关于该信号通路在胃酸分泌中的分子机制(S)知之甚少。在这里，我们证明了PKA与MST4合作，通过磷酸化Ser-66和Thr-567上的Ezrin来协调组胺诱导的酸分泌。组胺刺激激活PICA，PICA在Thr-178处使msT4磷酸化，然后促进MST4激酶活性。有趣的是，激活MST4然后磷酸化被PKA预磷酸化的Ezrin。重要的是，MST4对壁细胞的酸分泌很重要，因为抑制MST4或过度表达非磷酸化的MST4可以阻止组胺刺激引起的顶膜重组和质子泵转位。此外，过度表达MST4磷酸化缺陷的Ezrin会导致胃酸分泌的抑制。综上所述，这些结果定义了一种新的分子机制，将PKA-MST4-Ezrin信号级联与胃壁细胞的极化上皮分泌联系起来。
The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of the PKA cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin, whose phosphorylation at Ser-66 by PKA is required for parietal cell activation. However, little is known regarding the molecular mechanism(s) by which this signaling pathway operates in gastric acid secretion. Here we show that PKA cooperates with MST4 to orchestrate histamine-elicited acid secretion by phosphorylating ezrin at Ser-66 and Thr-567. Histamine stimulation activates PICA, which phosphorylates msT4 at Thr-178 and then promotes MST4 kinase activity. Interestingly, activated MST4 then phosphorylates ezrin prephosphorylated by PKA. Importantly, MST4 is important for acid secretion in parietal cells because either suppression of MST4 or overexpression of non-phosphorylatable MST4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, overexpressing MST4 phosphorylation-deficient ezrin results in an inhibition of gastric acid secretion. Taken together, these results define a novel molecular mechanism linking the PKA-MST4-ezrin signaling cascade to polarized epithelial secretion in gastric parietal cells.