MST4 phosphorylates ACAP4 to orchestrate apical membrane remodeling during gastric acid secretion [Signal Transduction]

The digestion in the stomach depends on acidification of the lumen. Histamine-elicited acid secretion is triggered by activation of 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 (Jiang et al., 2015. J. Biol. Chem. 290, 28272-28285). However, it remains uncharacterized how PKA-MST4-ezrin signaling axis operates the insertion of H,K-ATPases into the apical plasma membranes of gastric parietal cells. Here we show MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein (Ding et al., 2010. J. Biol. Chem. 285, 18769-18780), at Thr545. 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 Thr545 by mass spectrometric analyses. Importantly, phosphorylation of Thr545 is essential for acid secretion in parietal cells because either suppression of ACAP4 or over-expression of non-phosphorylatable ACAP4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, persistent over-expression of MST4 phosphorylation-deficient ACAP4 results in an inhibition of gastric acid secretion and a blockage of tubulovesicle fusion to the apical membranes. Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GAP domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change which enables ezrin-ACAP4 interaction. Taken together, these results define a novel molecular mechanism linking PKA-MST4-ACAP4 signaling cascade to polarized acid secretion in gastric parietal cells.

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