title: Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells.
abstract: 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 PKA, 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.
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Beijing University of Chinese Medicine, Beijing 100029, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: William W
authors.initials: WW
authors.lastname: Yao
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Jiying
authors.initials: J
authors.lastname: Jiang
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: Wendy Y
authors.initials: WY
authors.lastname: Yao
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Beijing University of Chinese Medicine, Beijing 100029, China; Airforce General Hospital, Beijing 100036, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Liu
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310.
authors.forename: Tarsha L
authors.initials: TL
authors.lastname: Ward
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Airforce General Hospital, Beijing 100036, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Liu
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address: dingx@bucm.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Ding
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,; Molecular Imaging Center, Atlanta Clinical and Translational Science Institute, Atlanta, Georgia 30310. Electronic address: xing1017@ustc.edu.cn.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: BUCM-USTC Joint Program in Cellular Dynamics and Anhui Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China,. Electronic address: xyao@msm.edu.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology*; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction; D000099149:Ezrin
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D006632:Histamine; D017346:Protein Serine-Threonine Kinases; D000099149:Ezrin
keywords: ACAP4; MST4; PKA; acid secretion; apical membrane; cell polarity; ezrin; protein kinase; protein phosphorylation; proton pump