title: Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation.
abstract: Infection of gastric mucosa by H. pylori triggers a pattern of inflammatory responses characterized by the rise in proinflammatory cytokine production, up-regulation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report on the role of MAPK/p38 and Rac1 in the regulation of H. pylori LPS-induced TGF-α ectodomain shedding and EGFR transactivation. We show that stimulation of gastric mucosal cells with the LPS, reflected in p38 phosphorylation, guanine nucleotide exchange factor Dock180 activation and the rise in Rac1-GTP level, is accompanied by the activation of membrane-associated metalloprotease, (TACE) also known as ADAM17, responsible for soluble TGF-α release. Further, we reveal that the LPS-induced TGF-α shedding and EGFR transactivation involves the TACE activation through phosphorylation by p38 that requires Rac1 participation. Moreover, we demonstrate that up-regulation in H. pylori LPS-elicited Rac1-GTP membrane translocation plays a pivotal role in recruitment of the activated p38 to the membrane for TACE activation through phosphorylation on Thr(735). Taken together, our findings provide strong evidence as to the essential function of Rac1 in TACE activation, TGF-α ectodomain shedding, and the EGFR transactivation.
authors.affiliation: Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA. slomiabr@sdm.rutgers.edu.
authors.forename: B L
authors.initials: BL
authors.lastname: Slomiany
authors.affiliation: Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA.
authors.forename: A
authors.initials: A
authors.lastname: Slomiany
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016211:Transforming Growth Factor alpha; C442865:lipopolysaccharide, Helicobacter pylori; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: EGFR transactivation; Gastric mucosa; H. pylori LPS; Rac1; TACE activation; TGF-α shedding; p38 MAPK