help button home button Am J Pathol International Conference on Pathology of Chest Diseases
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2008.070729 on June 26, 2008

Published online before print June 26, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ajpath.2008.070729v1
173/2/385    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Walsh, M. F.
Right arrow Articles by Basson, M. D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walsh, M. F.
Right arrow Articles by Basson, M. D.
(American Journal of Pathology. 2008;173:385-399.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070729

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

Mary F. Walsh, Dinakar R. Ampasala, James Hatfield, Richard Vander Heide, Silke Suer, Arun K. Rishi and Marc D. Basson

From the Departments of Surgery and Pathology, John D. Dingell Veterans Administration Medical Center and Wayne State University and the Barbara Ann Karmanos Cancer Institute, Detroit, Michigan

Focal adhesion kinase (FAK) regulates cell migration, proliferation, and apoptosis. FAK protein is reduced at the edge of migrating gut epithelial sheets in vitro, but it has not been characterized in restitutive gut mucosa in vivo. Here we show that FAK and activated phospho-FAK (FAK397) immunoreactivity was lower in epithelial cells immediately adjacent to human gastric and colonic ulcers in vivo, but dramatically increased in epithelia near the ulcers, possibly reflecting stimulation by growth factors absent in vitro. Transforming growth factor (TGF)-β, but not fibroblast growth factor, platelet-derived growth factor, or vascular endothelial growth factor, increased FAK levels in Caco-2 and IEC-6 cells. Epithelial immunoreactivity to TGF-β and phospho-Smad3 was also higher near the ulcers, varying in parallel with FAK. The TGF-β receptor antagonist SB431542 completely blocked TGF-β-induced Smad2/3 and p38 activation in IEC-6 cells. SB431542, the p38 antagonist SB203580, and siRNA-mediated reduction of Smad2 and p38{alpha} prevented TGF-β stimulation of both FAK transcription and translation (as measured via a FAK promoter-luciferase construct). FAK397 levels were directly related to total FAK protein expression. Although gut epithelial motility is associated with direct inhibition of FAK protein adjacent to mucosal wounds, TGF-β may increase FAK protein near but not bordering mucosal ulcers via Smad2/3 and p38 signals. Our results show that regulation of FAK expression may be as important as FAK phosphorylation in critically influencing gut epithelial cell migration after mucosal injury.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by the American Society for Investigative Pathology.