Journal
EXPERIMENTAL CELL RESEARCH
Volume 315, Issue 19, Pages 3336-3344Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2009.05.020
Keywords
Clostridium difficile; Toxin A; Paxillin; Focal adhesion kinase; Transepithelial resistance; Colitis; Signal transduction; Rho family proteins
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Funding
- National Institutes of Health [DK R37-03458, PO-1 DK 33506]
- Korea Research Foundation Grant (MOEHRD) [KRF-2008-331-E00098]
- Korea Healthcare Technology RD Project
- Ministry of Health and Welfare, Republic of Korea [A080933]
- Korea Health Promotion Institute [A080933] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Clostridium difficile toxin A impairs tight junction function of colonocytes by glucosylation of Rho family proteins causing actin filament disaggregation and cell rounding. We investigated the effect of toxin A on focal contact formation by assessing its action on focal adhesion kinase (FAK) and the adapter protein paxillin. Exposure of NCM460 human colonocytes to toxin A for 1 h resulted in complete dephosphorylation of FAK and paxillin, while protein tyrosine phosphatase activity was reduced. Blockage of toxin A-associated glucosyltransferase activity by co-incubation with UDP-2' 3' dialdehyde did not reduce toxin A-induced FAK and paxillin dephosphorylation. GST-pull down and in vitro kinase activity experiments demonstrated toxin A binding directly to the catalytic domain of Src with suppression of its kinase activity. Direct binding of toxin A to Src, independent of any effect on protein tyrosine phosphatase or Rho glucosylation, inhibits Src kinase activity followed by FAK/paxillin inactivation. These mechanisms may contribute to toxin A inhibition of colonocyte focal adhesion that occurs in human colonic epithelium exposed to toxin A. (C) 2009 Elsevier Inc. All rights reserved.
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