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Am J Physiol Gastrointest Liver Physiol 287: G886-G898, 2004. First published June 10, 2004; doi:10.1152/ajpgi.00065.2004
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MUCOSAL BIOLOGY

Epithelial cell spreading induced by hepatocyte growth factor influences paxillin protein synthesis and posttranslational modification

Ann M. Hopkins,1,* Matthias Bruewer,1,2,* G. Thomas Brown,1 A’Drian A. Pineda,1 Julie J. Ha,1 L. Matthew Winfree,1 Shaun V. Walsh,1 Brian A. Babbin,1 and Asma Nusrat1

1Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322; and 2Department of General Surgery, University of Muenster, 48149 Muenster, Germany

Submitted 9 February 2004 ; accepted in final form 3 June 2004

Superficial wounds in the gastrointestinal tract rapidly reseal by coordinated epithelial cell migration facilitated by cytokines such as hepatocyte growth factor (HGF)/scatter factor released in the wound vicinity. However, the mechanisms by which HGF promotes physiological and pathophysiologic epithelial migration are incompletely understood. Using in vitro models of polarized T84 and Caco-2 intestinal epithelia, we report that HGF promoted epithelial spreading and RhoA GTPase activation in a time-dependent manner. Inducible expression of enhanced green fluorescent protein-tagged dominant-negative RhoA significantly attenuated HGF-induced spreading. HGF expanded a zone of partially flattened cells behind the wound edge containing basal F-actin fibers aligned in the direction of spreading. Concomitantly, plaques positive for the focal adhesion protein paxillin were enhanced. HGF induced an increase in the translation of paxillin and, to a lesser extent, {beta}1-integrin. This was independent of cell-matrix adhesion through {beta}1-integrin. Subcellular fractionation revealed increased cosedimentation of paxillin with plasma membrane-containing fractions following HGF stimulation, without corresponding enhancements in paxillin coassociation with {beta}1 integrin or actin. Tyrosine phosphorylation of paxillin was reduced by HGF and was sensitive to the Src kinase inhibitor PP2. With these taken together, we propose that HGF upregulates a free cytosolic pool of paxillin that is unaffiliated with either the cytoskeleton or focal cell-matrix contacts. Thus early spreading responses to HGF may partly relate to increased paxillin availability for incorporation into, and turnover within, dynamic cytoskeletal/membrane complexes whose rapid and transient adhesion to the matrix drives migration.

epithelium; cell migration; actin; focal complexes


Address for reprint requests and other correspondence: A. Nusrat, Dept. of Pathology and Laboratory Medicine, Emory Univ., Rm. 105E, Whitehead Research Bldg., 615 Michael St., Atlanta, GA 30322 (E-mail: anusrat{at}emory.edu)




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