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Am J Physiol Cell Physiol (October 15, 2008). doi:10.1152/ajpcell.00232.2008
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Submitted on April 28, 2008
Revised on September 23, 2008
Accepted on October 13, 2008

Rac1 Promotes Intestinal Epithelial Restitution by Increasing Ca2+ Influx through Interaction with Phospholipase C-{gamma}1 after Wounding

Jaladanki N Rao1, Stephen V Liu2, Tongtong Zou3, Lan Liu4, Lan Xiao5, Xian Zhang2, Emily Bellavance2, Jason X.-J. Yuan6, and Jian-Ying Wang7*

1 University of Maryland
2 University of MD
3 University ofr MD
4 Univ of MD
5 University of Maryland and VAMC
6 University of Califormia, San Diego
7 University of Maryland School of Medicine

* To whom correspondence should be addressed. E-mail: JWANG{at}smail.umaryland.edu.

Intestinal mucosal restitution occurs as a consequence of epithelial cell migration and reseals superficial wounds after injury. This rapid reepithelialization is mediated in part by a phospholipase C-{gamma}1 (PLC-{gamma}1)-induced Ca2+ signaling, but the exact mechanism underlying such signaling and its regulation remains elusive. The small GTP-binding protein Rac1 functions as a pivotal regulator of several signaling networks and plays an important role in regulating cell motility. The current study tests the hypothesis that Rac1 modulates intestinal epithelial cell (IEC) migration after wounding by altering PLC-{gamma}1-induced Ca2+ signaling. Inhibition of Rac1 activity by treatment with its inhibitor NSC23766 or Rac1 silencing with small interfering RNA decreased store depletion-induced Ca2+ influx and suppressed cell migration during restitution, whereas ectopic overexpression of Rac1 increased Ca2+ influx and promoted cell migration. Rac1 physically interacted with PLC-{gamma}1 and formed Rac1/PLC-{gamma}1 complex in IECs. PLC-{gamma}1 silencing in cells overexpressing Rac1 prevented stimulation of store depletion-induced Ca2+ influx and cell migration after wounding. Polyamine depletion inhibited expression of both Rac1 and PLC-{gamma}1, decreased Rac1/PLC-{gamma}1 complex levels, reduced Ca2+ influx, and repressed cell migration. Overexpression of Rac1 alone failed to rescue Ca2+ influx after store depletion and cell migration in polyamine-deficient cells, because it did not alter PLC-{gamma}1 levels. These results indicate that Rac1 promotes intestinal epithelial cell migration after wounding by increasing Ca2+ influx as a result of its interaction with PLC-{gamma}1.




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