TY - JOUR

T1 - A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers

AU - Xu, Rui

AU - Höß, Carsten

AU - Swiercz, Jakub M

AU - Brandt, Dominique T

AU - Lutz, Veronika

AU - Petersen, Natalia

AU - Li, Rui

AU - Zhao, Dandan

AU - Oleksy, Arkadiusz

AU - Creigh-Pulatmen, Tilbe

AU - Trokter, Martina

AU - Fedorova, Marina

AU - Atzberger, Ann

AU - Strandby, Rune B

AU - Olsen, August A.

AU - Achiam, Michael P.

AU - Matthews, David

AU - Huber, Magdalena

AU - Gröne, Hermann-Josef

AU - Offermanns, Stefan

AU - Worzfeld, Thomas

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Adhesion Molecules

KW - GTPase-Activating Proteins

KW - Gastrins/adverse effects

KW - Humans

KW - Mice

KW - Nerve Tissue Proteins

KW - Peptic Ulcer/chemically induced

KW - Semaphorins

KW - Signal Transduction

U2 - 10.1126/scitranslmed.abf1922

DO - 10.1126/scitranslmed.abf1922

M3 - Journal article

C2 - 35857828

VL - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 654

M1 - eabf1922

ER -