MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion

Yuan，Xiao1; Yao，Phil Y.2,3; Jiang，Jiying1; Zhang，Yin1,2; Su，Zeqi1,2; Yao，Wendy3; Wang，Xueying1; Gui，Ping1; Mullen，McKay3; Henry，Calmour3; Ward，Tarsha1,3; Wang，Wenwen1,3; Brako，Larry3; Tian，Ruijun1,5; Zhao，Xuannv2; Wang，Fengsong1,3,4; Cao，Xinwang3,4; Wang，Dongmei1; Liu，Xing1,3; Ding，Xia2; Yao，Xuebiao1,3

2017

10.1074/JBC.M117.808212

JOURNAL OF BIOLOGICAL CHEMISTRY   影响因子和分区

0021-9258

1083-351X

Digestion in the stomach depends on acidification of the lumen. Histamine-elicited acid secretion 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. Our recent study revealed the functional role of PKA-MST4 - ezrin signaling axis in histamine-elicited acid secretion. However, it remains uncharacterized how the PKA-MST4 - ezrin signaling axis operates the insertion of H,KATPases into the apical plasma membranes of gastric parietal cells. Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr. Histamine stimulation activates MST4 and promotes MST4 interaction with ACAP4. ACAP4 physically interacts with MST4 and is a cognate substrate of MST4 during parietal cell activation. The phosphorylation site of ACAP4 by MST4 was mapped to Thr by mass spectrometric analyses. Importantly, phosphorylation of Thr is essential for acid secretion in parietal cells because either suppression of ACAP4 or overexpression of non-phosphorylatable ACAP4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, persistent overexpression of MST4 phosphorylation-deficient ACAP4 results in inhibition of gastric acid secretion and blockage of tubulovesicle fusion to the apical membranes. Significantly, phosphorylation of Thr enables ACAP4 to interact with ezrin. Given the location of Thr between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction. Taken together, these results define a novel molecular mechanism linking the PKA-MST4 -ACAP4 signaling cascade to polarized acid secretion in gastric parietal cells.

SCI ; EI

英语

其他

National Basic Research Program of China (973 Program)[2016YFA0100500];National Basic Research Program of China (973 Program)[2017YFA0503600];

WOS:000412109400017

20201608457952

Mass spectrometry ; Signaling ; Cell signaling ; Chemical activation ; Cytology ; Cell membranes ; Physiology ; Proteins

Biomedical Engineering:461.1 ; Biological Materials and Tissue Engineering:461.2 ; Biology:461.9 ; Chemistry:801 ; Chemical Reactions:802.2 ; Chemical Products Generally:804 ; Organic Compounds:804.1

BIOLOGY & BIOCHEMISTRY

2-s2.0-85031686349

Scopus

1.BUCM-USTC Collaborative Center for Parietal Cell Research,CAS Center for Excellence in Molecular Cell Science,University of Science and Technology of China,Hefei,230027,China
2.Beijing University of Chinese Medicine,Beijing,100029,China
3.Keck Center for Cellular Dynamics,Morehouse School of Medicine,Atlanta,30310,United States
4.Department of Biochemistry,Anhui Medical University,Hefei,230027,China
5.Southern University of Science and Technology,Shenzhen,518055,China

Yuan，Xiao,Yao，Phil Y.,Jiang，Jiying,et al. MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292(39):16174-16187.

Yuan，Xiao.,Yao，Phil Y..,Jiang，Jiying.,Zhang，Yin.,Su，Zeqi.,...&Yao，Xuebiao.(2017).MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion.JOURNAL OF BIOLOGICAL CHEMISTRY,292(39),16174-16187.

Yuan，Xiao,et al."MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion".JOURNAL OF BIOLOGICAL CHEMISTRY 292.39(2017):16174-16187.