TITLE:
Porphyromonas gingivalis-Stimulated TACE Activation for TGF-α Ectodomain Shedding and EGFR Transactivation in Salivary Gland Cells Requires Rac1-Dependent p38 MAPK Membrane Localization
AUTHORS:
Bronislaw L. Slomiany, Amalia Slomiany
KEYWORDS:
P. gingivalis LPS, Oral Mucosa, p38 MAPK, TGF-α, TACE Activation, Rac1, EGFR Transactivation
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.3 No.11,
November
6,
2015
ABSTRACT: Oral mucosal inflammatory responses to P. gingivalis and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in proinflammatory cytokine production, up-regu- lation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report that stimulation of salivary gland acinar cells with P. gingivalis LPS leads to p38 MAPK-dependent release of soluble TGF-α ligand and the increase in EGFR phosphorylation. Further, we show that the LPS-induced TGF-α shedding and EGFR transactivation involve the activation of membrane-associated metalloprotease, TACE also known as ADAM17, through phosphorylation by p38 MAPK, and require Rac1 participation. Moreover, we demonstrate that blocking the Rac1 activation leads to the suppression in the membrane translocation of Rac1 as well as p38, thus indicating that the LPS-elicited p38 membrane recruitment for TACE phosphorylation requires colocalization with Rac1. Hence, our findings imply that Rac1 membrane translocation serves as an essential platform for the localization of p38 with TACE, TGF-α ectodomain shedding, and the EGFR activation.