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  A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers

Xu, R., Hoess, C., Swiercz, J. M., Brandt, D. T., Lutz, V., Petersen, N., et al. (2022). A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers. SCIENCE TRANSLATIONAL MEDICINE, 14(654): eabf1922. doi:10.1126/scitranslmed.abf1922.

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Xu, Rui1, Author           
Hoess, Carsten, Author
Swiercz, Jakub M.1, Author           
Brandt, Dominique T., Author
Lutz, Veronika, Author
Petersen, Natalia, Author
Li, Rui1, Author           
Zhao, Dandan, Author
Oleksy, Arkadiusz, Author
Creigh-Pulatmen, Tilbe, Author
Trokter, Martina, Author
Fedorova, Marina, Author
Atzberger, Ann2, Author           
Strandby, Rune B., Author
Olsen, August A., Author
Achiam, Michael P., Author
Matthews, David, Author
Huber, Magdalena, Author
Groene, Hermann-Josef, Author
Offermanns, Stefan1, Author           
Worzfeld, Thomas1, Author            more..
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              
2Facs Service, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591706              

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 Abstract: Peptic ulcer disease is a frequent clinical problem with potentially serious complications such as bleeding or perforation. A decisive factor in the pathogenesis of peptic ulcers is gastric acid, the secretion of which is controlled by the hormone gastrin released from gastric G cells. However, the molecular mechanisms regulating gastrin plasma concentrations are poorly understood. Here, we identified a semaphorin-plexin signaling pathway that operates in gastric G cells to inhibit gastrin expression on a transcriptional level, thereby limiting food-stimulated gastrin release and gastric acid secretion. Using a systematic siRNA screening approach combined with biochemical, cell biology, and in vivo mouse experiments, we found that the RasGAP protein Rasal1 is a central mediator of plexin signal transduction, which suppresses gastrin expression through inactivation of the small GTPase R-Ras. Moreover, we show that Rasal1 is pathophysiologically relevant for the pathogenesis of peptic ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), a main risk factor of peptic ulcers in humans. Last, we show that application of recombinant semaphorin 4D alleviates peptic ulcer disease in mice in vivo, demonstrating that this signaling pathway can be harnessed pharmacologically. This study unravels a mode of G cell regulation that is functionally important in gastric homeostasis and disease.

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 Dates: 2022-07-20
 Publication Status: Published online
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Title: SCIENCE TRANSLATIONAL MEDICINE
Source Genre: Journal
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Pages: - Volume / Issue: 14 (654) Sequence Number: eabf1922 Start / End Page: - Identifier: ISSN: 1946-6234