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J. Biol. Chem., Vol. 282, Issue 42, 30341-30345, October 19, 2007

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Janus Kinase 3 Regulates Interleukin 2-induced Mucosal Wound Repair through Tyrosine Phosphorylation of Villin^*

Narendra Kumar¹, Jayshree Mishra, Vishal S. Narang, and Christopher M. Waters

From the Departments of Physiology and Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Janus kinase 3 (Jak3) is a non-receptor tyrosine kinase known to be expressed in hematopoietic cells. Studies of whole organ homogenates show that Jak3 is also expressed in the intestines of both human and mice. However, neither its expression nor its function has been defined in intestinal epithelial enterocytes. The present studies demonstrate that functional Jak3 is expressed in human intestinal enterocytes HT-29 Cl-19A and Caco-2 and plays an essential role in the intestinal epithelial wound repair process in response to interleukin 2 (IL-2). Exogenous IL-2 enhanced the wound repair of intestinal enterocytes in a dose-dependent manner. Activation by IL-2 led to rapid tyrosine phosphorylation and redistribution of Jak3. IL-2-stimulated redistribution of Jak3 was inhibited by the Jak3-specific inhibitor WHI-P131. IL-2 also induced Jak3-dependent redistribution of the actin cytoskeleton in migrating cells. In these cells Jak3 interacted with the intestinal and renal epithelial cell-specific cytoskeletal protein villin in an IL-2-dependent manner. Inhibition of Jak3 activation resulted in loss of tyrosine phosphorylation of villin and a significant decrease in wound repair of the intestinal epithelial cells. Previously, we had shown that tyrosine phosphorylation of villin is important for cytoskeletal remodeling and cell migration. The present study demonstrates a novel pathway in intestinal enterocytes in which IL-2 enhances intestinal wound repair through mechanisms involving Jak3 and its interactions with villin.

Received for publication, December 27, 2006 , and in revised form, April 24, 2007.

^* These studies were supported by a research fellowship award from the Crohn's Colitis Foundation of America (to N. K.) and by NHLBI/National Institutes of Health Grant HL-064981 (to C. M. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Physiology, University of Tennessee, Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-5778; Fax: 901-448-7126; E-mail: nkumar{at}utmem.edu.

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