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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Repetitive deformation activates Src-independent FAK-dependent ERK motogenic signals in human Caco-2 intestinal epithelial cells

¹Surgical Service, John D. Dingell Veterans Affairs Medical Center, and Departments of ²Surgery, ³Anesthesiology, and ⁴Anatomy and Cell Biology, Wayne State University, Detroit, Michigan

Submitted 18 January 2008 ; accepted in final form 18 April 2008

Repetitive deformation due to villous motility or peristalsis may support the intestinal mucosa, stimulating intestinal epithelial proliferation under normal circumstances and restitution in injured and inflamed mucosa rich in tissue fibronectin. Cyclic strain enhances Caco-2 and IEC-6 intestinal epithelial cell migration across fibronectin via ERK. However, the upstream mediators of ERK activation are unknown. We investigated whether Src and FAK mediate strain-induced ERK phosphorylation and migration in human Caco-2 intestinal epithelial cells on fibronectin. Monolayers on tissue fibronectin-precoated membranes were subjected to an average 10% repetitive deformation at 10 cycles/min. Phosphorylation of Src-Tyr⁴¹⁸, FAK-Tyr³⁹⁷-Tyr⁵⁷⁶-Tyr⁹²⁵, and ERK were significantly increased by deformation. The stimulation of wound closure by strain was prevented by Src blockade with PP2 (10 µmol/l) or specific short interfering (si)RNA. Src inhibition also prevented strain-induced FAK phosphorylation at Tyr³⁹⁷ and Tyr⁵⁷⁶ but not FAK-Tyr⁹²⁵ or ERK phosphorylation. Reducing FAK by siRNA inhibited strain-induced ERK phosphorylation. Transfection of NH₂-terminal tyrosine phosphorylation-deficient FAK mutants Y397F, Y576F-Y577F, and Y397F-Y576F-Y577F did not prevent the activation of ERK2 by cyclic strain, but a FAK mutant at the COOH terminal (Y925F) prevented the strain-induced activation of ERK2. Although the Y397F-Y576F-Y577F FAK construct exhibited less basal FAK-Tyr⁹²⁵ phosphorylation under static conditions, it nevertheless exhibited increased FAK-Tyr⁹²⁵ phosphorylation in response to strain. These results suggest that repetitive deformation stimulates intestinal epithelial motility across fibronectin in a manner that requires both Src activation and a novel Src-independent FAK-Tyr⁹²⁵-dependent pathway that activates ERK. This pathway may be an important target for interventions to promote mucosal healing in settings of intestinal ileus or fasting.

migration; cyclic strain; intestine; mechanotransduction; signaling

This article has been cited by other articles:

				C. P. Gayer, L. S. Chaturvedi, S. Wang, B. Alston, T. L. Flanigan, and M. D. Basson Delineating the signals by which repetitive deformation stimulates intestinal epithelial migration across fibronectin Am J Physiol Gastrointest Liver Physiol, April 1, 2009; 296(4): G876 - G885. [Abstract] [Full Text] [PDF]