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

Jiang, Hao; Wang, Wenwen; Zhang, Yin; Yao, William; Jiang, Jiying; Qin, Bo; Yao, Wendy; Liu, Fusheng; Wu, Huihui; Ward, Tarsha; Chen, Chun-Wei; Liu, Lifang; Ding, Xia; Liu, Xing; Yao, Xuebiao

doi:10.1074/jbc.m115.668855

Cited by 17 publications

(28 citation statements)

References 27 publications

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“…GSTAurora B dephosphorylation was determined by measuring the dephosphorylation in the presence of PP1/Sds22 and subtracted from the experiments in the absence of PP1/Sds22. The data were fit to the Michaelis-Menten equation to derive apparent V max and K m with the GraphPad Prism software as described previously (50).…”

Section: Volume 291 • Number 40 • September 30 2016mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr 232 ) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr 232 of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

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Section: Volume 291 • Number 40 • September 30 2016mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…With its expression dynamically responding to bacterial infection, MST4 kinase can directly phosphorylate TRAF6 to confine macrophage-mediated inflammation, therefore avoiding tissue damage caused by immune overaction (Jiao et al, 2015). Recently, MST4 has been found to orchestrate gastric acid secretion by phosphorylating ACAP4 and Ezrin (Jiang et al, 2015; Yuan et al, 2017). In addition, MST4 stimulates autophagy via phosphorylation-dependent activation of ATG4B in glioblastoma (Huang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Nie

Chen

et al. 2020

Journal of Experimental Medicine

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Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.

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“…1A, bottom panel, lane 1). Our mass spectrometric analyses identified the 45-kDa polypeptide as MST4, a characterized cell polarity kinase interacting with ezrin in cell polarity establishment and parietal cell acid secretion (11). Western blotting analyses validated that the actin-binding protein ezrin also exists in the immunoprecipitates of ACAP4 in secreting parietal cells (Fig.…”

Section: Identification Of a Novel Mst4 -Acap4 Complex In Secreting Gmentioning

confidence: 53%

“…In these parietal cells, H,K-ATPasecontaining tubulovesicles failed to fuse with the apical membrane, suggesting an essential role of ezrin in tubulovesicle docking. Our recent studies showed that PKA cooperates with MST4 to orchestrate histamine-elicited acid secretion by phosphorylating ezrin at Ser 66 and Thr 567 , respectively (11). Histamine stimulation activates PKA, which phosphorylates MST4 at Thr 178 and then promotes MST4 kinase activity.…”

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confidence: 99%

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

Yuan

Yao

Jiang

et al. 2017

Journal of Biological Chemistry

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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,K-ATPases 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.

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

Cited by 17 publications

References 27 publications

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

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

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