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Am J Physiol Gastrointest Liver Physiol (November 6, 2003). doi:10.1152/ajpgi.00262.2003
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Submitted on June 16, 2003
Accepted on November 5, 2003

Collagen IV regulates Caco-2 migration and ERK activation via {alpha}1{beta}1 and {alpha}2{beta}1 integrin-dependent Src kinase activation

Matthew A. Sanders1 and Marc D. Basson1*

1 Department of Surgery, Wayne State University, Detroit, Michigan, USA; Department of Surgery, John D. Dingell VA Medical Center, Detroit, Michigan, USA

* To whom correspondence should be addressed. E-mail: marc.basson{at}med.va.gov.

Our previous work indicates intestinal epithelial cell ERK activation by collagen IV, a major component of the intestinal epithelial basement membrane, requires focal adhesion kinase (FAK) and suggests FAK and ERK may have important roles in regulating intestinal epithelial cell migration. We therefore sought to identify FAK downstream targets regulating intestinal epithelial cell spreading, migration, and ERK activation on collagen IV and the integrins involved. The Src kinase inhibitor PP2 inhibited Src Y416 phosphorylation on collagen IV and both PP2 and dominant negative Src strongly inhibited collagen IV ERK activation in Caco-2 intestinal epithelial cells. Phosphorylation of the Grb2 binding site FAK Y925 was stimulated by collagen IV, required FAK Y397 autophosphorylation and was inhibited by PP2. Additionally, FAK Y925F expression blocked ERK activation by collagen IV. {alpha}1{beta}1 or {alpha}2{beta}1 integrin blockade with {alpha}1 or {alpha}2 integrin subunit antibodies indicated either integrin can mediate adhesion, cell spreading, and FAK, Src, and ERK activation on collagen IV. Both dominant negative Src and PP2 inhibited cell spreading on collagen IV. Expression of a dominant negative form of the Src phosphorylation substrate p130Cas, however, did not affect cell spreading. Though PP2 and the ERK inhibitor PD98059 both significantly inhibited migration on collagen IV, PP2 inhibited migration much more strongly than PD98059, which completely inhibited ERK activation by collagen IV. These results suggest a pathway for collagen IV activation of ERK requiring Src phosphorylation of FAK Y925 that has not been previously described for this matrix protein and suggests either {alpha}1{beta}1 or {alpha}2{beta}1 integrins can regulate Caco-2 cell spreading and ERK activation on collagen IV via Src. Additionally, these results suggest Src is an important regulator of Caco-2 migration on collagen IV and regulates migration primarily through ERK-independent pathways.




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