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J. Biol. Chem., Vol. 282, Issue 1, 14-28, January 5, 2007

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Repetitive Deformation Activates Focal Adhesion Kinase and ERK Mitogenic Signals in Human Caco-2 Intestinal Epithelial Cells through Src and Rac1^*

Lakshmi S. Chaturvedi^¶, H. Michael Marsh^¶, Xun Shang^||, Yi Zheng^||, and Marc D. Basson^¶**1

From the Surgical Service, John D. Dingell Veterans Affairs Medical Center and Departments of Surgery, ^¶Anesthesiology, ^**Anatomy and Cell Biology, Wayne State University, Detroit, Michigan 48201 and ^||Division of Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229

Intestinal epithelial cells are subject to repetitive deformation during peristalsis and villous motility, whereas the mucosa atrophies during sepsis or ileus when such stimuli are abnormal. Such repetitive deformation stimulates intestinal epithelial proliferation via focal adhesion kinase (FAK) and extracellular signal-regulated kinases (ERK). However, the upstream mediators of these effects are unknown. We investigated whether Src and Rac1 mediate deformation-induced FAK and ERK phosphorylation and proliferation in human Caco-2 and rat IEC-6 intestinal epithelial cells. Cells cultured on collagen-I were subjected to an average 10% cyclic strain at 10 cycles/min. Cyclic strain activated Rac1 and induced Rac1 translocation to cell membranes. Mechanical strain also induced rapid sustained phosphorylation of c-Src at Tyr⁴¹⁸, Rac1 at Ser⁷¹, FAK at Tyr³⁹⁷ and Tyr⁵⁷⁶, and ERK1/2 at Thr²⁰²/Tyr²⁰⁴. The mitogenic effect of cyclic strain was blocked by inhibition of Src (PP2 or short interfering RNA) or Rac1 (NSC23766). Src or Rac1 inhibition also prevented strain-induced FAK phosphorylation at Tyr⁵⁷⁶ and ERK phosphorylation but not FAK phosphorylation at Tyr³⁹⁷. Reducing FAK using short interfering RNA blocked strain-induced mitogenicity and attenuated ERK phosphorylation but not Src or Rac1 phosphorylation. Src inhibition blocked strain-induced Rac1 phosphorylation, but Rac inhibition did not alter Src phosphorylation. Transfection of a two-tyrosine phosphorylation-deficient FAK mutant Y576F/Y577F prevented activation of cotransfected myc-ERK2 by cyclic strain. Repetitive deformation induced by peristalsis or villus motility may support the gut mucosa by a pathway involving Src, Rac1, FAK, and ERK. This pathway may present important targets for interventions to prevent mucosal atrophy during prolonged ileus or fasting.

Received for publication, June 16, 2006 , and in revised form, October 12, 2006.

^* This work was supported in part by a Veterans Affairs merit research award (to M. D. B.), National Institutes of Health Grant RO1 DK067257 (to M. D. B.), and developmental funds from the Department of Anesthesiology, Wayne State University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Chief, Surgical Service (11S), John D. Dingell Veterans Affairs Medical Center, 4646 John R. St., Detroit, MI 48201. Tel.: 313-576-3598; Fax: 313-576-1002; E-mail: marc.basson{at}va.gov.

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