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J. Biol. Chem., Vol. 282, Issue 42, 30643-30657, October 19, 2007

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CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

ROLE OF c-Met, Tiam1/Rac1, DYNAMIN 2, AND CORTACTIN^*

From the Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637

The preservation of vascular endothelial cell (EC) barrier integrity is critical to normal vessel homeostasis, with barrier dysfunction being a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that preserve or restore vascular integrity have important therapeutic implications. In this study, we explored the regulation of hepatocyte growth factor (HGF)-mediated enhancement of EC barrier function via CD44 isoforms. We observed that HGF promoted c-Met association with CD44v10 and recruitment of c-Met into caveolin-enriched microdomains (CEM) containing CD44s (standard form). Treatment of EC with CD44v10-blocking antibodies inhibited HGF-mediated c-Met phosphorylation and c-Met recruitment to CEM. Silencing CD44 expression (small interfering RNA) attenuated HGF-induced recruitment of c-Met, Tiam1 (a Rac1 exchange factor), cortactin (an actin cytoskeletal regulator), and dynamin 2 (a vesicular regulator) to CEM as well as HGF-induced trans-EC electrical resistance. In addition, silencing Tiam1 or dynamin 2 reduced HGF-induced Rac1 activation, cortactin recruitment to CEM, and EC barrier regulation. We observed that both HGF- and high molecular weight hyaluronan (CD44 ligand)-mediated protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was significantly reduced in CD44 knock-out mice, thus validating these in vitro findings in an in vivo murine model of inflammatory lung injury. Taken together, these results suggest that CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin.

Received for publication, March 26, 2007 , and in revised form, August 14, 2007.

^* This work was supported in part by Ruth L. Kirschstein National Research Award F32 HL68472 and Program Project Grant HL58064 from the National Institutes of Health and by National Scientist Development Grant 0730277N from the American Heart Association. 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., W604, Chicago, IL 60637. Tel.: 773-834-3163; Fax: 773-702-4427; E-mail: jgarcia{at}medicine.bsd.uchicago.edu.

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