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Am J Physiol Gastrointest Liver Physiol 286: G547-G557, 2004. First published November 6, 2003; doi:10.1152/ajpgi.00262.2003
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MUCOSAL BIOLOGY

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. Sanders and Marc D. Basson

Departments of Surgery, Wayne State University, and John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201-1932

Submitted 16 June 2003 ; accepted in final form 5 November 2003

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. Both dominant-negative Src and Src inhibitor PP2 strongly inhibited collagen IV ERK activation in Caco-2 intestinal epithelial cells. Collagen IV stimulated Grb2 binding site FAK Y925 phosphorylation, which was inhibited by PP2 and required FAK Y397 autophosphorylation. Additionally, FAK Y925F expression blocked collagen IV ERK activation. {alpha}1{beta}1- Or {alpha}2{beta}1-integrin blockade with {alpha}1- or {alpha}2-integrin subunit antibodies indicated that either integrin can mediate adhesion, cell spreading, and FAK, Src, and ERK activation on collagen IV. Both dominant-negative Src and PP2 inhibited Caco-2 spreading on collagen IV. PP2 inhibited p130Cas tyrosine phosphorylation, but dominant-negative p130Cas did not inhibit cell spreading. PP2 inhibited Caco-2 migration on collagen IV much more strongly than the mitogen-activated protein kinase kinase inhibitor PD-98059, which completely inhibited collagen IV ERK activation. These results suggest a pathway for collagen IV ERK activation requiring Src phosphorylation of FAK Y925 not previously described for this matrix protein and suggest either {alpha}1{beta}1- or {alpha}2{beta}1-integrins can regulate Caco-2 spreading and ERK activation on collagen IV via Src. Additionally, these results suggest Src regulates Caco-2 migration on collagen IV primarily through ERK-independent pathways.

extracellular matrix; focal adhesion kinase; cell spreading; cell adhesion


Address for reprint requests and other correspondence: M. Basson, Chief, Surgical Service (11 Surg), John D. Dingell Veterans Affairs Medical Center, 4646 John R Street, Detroit, MI 48201-1932 (E-mail: marc.basson{at}med.va.gov).




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