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TRANSLATIONAL PHYSIOLOGY

Rac1 promotes intestinal epithelial restitution by increasing Ca²⁺ influx through interaction with phospholipase C-1 after wounding

¹Cell Biology Group, Department of Surgery and ²Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland; ³Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; and ⁴Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 28 April 2008 ; accepted in final form 13 October 2008

ABSTRACT

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-1 (PLC-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 migration after wounding by altering PLC-1-induced Ca²⁺ signaling. Inhibition of Rac1 activity by treatment with its inhibitor NSC-23766 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-1 and formed Rac1/PLC-1 complex in intestinal epithelial cells. PLC-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-1, decreased Rac1/PLC-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-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-1.

mucosal injury; early rapid mucosal repair; polyamines; cell migration; capacitative Ca²⁺ entry; cdx2 gene; small guanosine 5'-triphosphate-binding proteins

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