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1 Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
2 Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA; Department of General Surgery, University of Muenster, Muenster, Germany
* To whom correspondence should be addressed. E-mail: anusrat{at}emory.edu.
Superficial wounds in the gastrointestinal tract rapidly reseal by coordinated epithelial cell migration,
facilitated by cytokines such as hepatocyte growth factor/scatter factor (HGF) released in the wound
vicinity. However, the mechanisms by which HGF promotes physiologic 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 EGFP-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, 
-1 integrin. This was independent of cell-matrix adhesion through -1
integrin. Subcellular fractionation revealed increased co-sedimentation of paxillin with plasma
membrane-containing fractions following HGF stimulation, without corresponding enhancements in
paxillin co-association with -1 integrin or actin. Tyrosine phosphorylation of paxillin was reduced by
HGF and was sensitive to the Src kinase inhibitor PP2. Taken together, we propose that HGF upregulates
a free cytosolic pool of paxillin which 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.
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