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HIGHLIGHT Volume 315, Number 19, November 15, 2009 Clostridium difficile toxin A binds colonocyte Src causing dephosphorylation of focal adhesion kinase and paxillin. By Ho Kim, Sang Hoon Rhee, Charalabos Pothoulakis, and J. Thomas LaMont. . . . . . . . . . . . . . . . . . . . . . . . . . . 3336 Clostridium difficile toxin A triggers colitis in humans by causing detachment of epithelial cells and impairment of barrier function related to actin disaggregation resulting from Rho glucosylation. We studied disruption of focal adhesions in colonocytes treated with toxin A. Toxin A caused complete dephosphorylation of FAK/paxillin which resulted from direct binding of toxin A to the catalytic domain of Src leading to reduction of its kinase activity. This effect was unrelated to the ability of toxin A to glucosylate Rho proteins in colonocytes. Our findings provide a novel pathophysiologic mechanism for the action of toxin A on the colon, which results in functional impairment of tight junction function.