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J. Biol. Chem., Vol. 282, Issue 2, 1265-1280, January 12, 2007

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Hyaluronan-CD44 Interaction with Neural Wiskott-Aldrich Syndrome Protein (N-WASP) Promotes Actin Polymerization and ErbB2 Activation Leading to -Catenin Nuclear Translocation, Transcriptional Up-regulation, and Cell Migration in Ovarian Tumor Cells^*

From the Department of Medicine, University of California, Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121

In this study we have investigated the interaction of hyaluronan (HA) and CD44 with the neuronal Wiskott-Aldrich syndrome protein (N-WASP) in regulating actin polymerization and ErbB2/-catenin signaling in human ovarian tumor cells (SK-OV-3.ipl cells). Biochemical and immunological analyses indicate that N-WASP is expressed in SK-OV-3.ipl cells and that the binding of HA stimulates N-WASP association with CD44 and Arp2/Arp3 leading to filamentous actin formation and ovarian tumor cell migration. In addition, HA binding promotes CD44-N-WASP association with ErbB2 and activates ErbB2 kinase activity that in turn increases phosphorylation of the cytoskeletal protein, -catenin. Subsequently, phosphorylated -catenin is transported into the nucleus leading to -catenin-mediated TCF/LEF-transcriptional co-activation. Because HA-induced -catenin phosphorylation, nuclear translocation, and TCF/LEF transcriptional activation is effectively blocked by the ErbB2 inhibitor, AG825, we conclude that HA/CD44-N-WASP-associated ErbB2 activation is required for -catenin-mediated signaling events. Transfection of SK-OV-3.ipl cells with N-WASP-VCA (verpolin homology, cofilin homology, and acidic domain) fragment cDNA not only blocks HA/CD44-induced N-WASP-Arp2/3 complex formation but also inhibits actin polymerization/F-actin assembly and tumor cell migration. Overexpression of the N-WASP-VCA domain also significantly reduces HA-induced ErbB2 recruitment to CD44, diminishes -catenin phosphorylation/nuclear translocation, and abrogates TCF/LEF-specific transcriptional co-activation by -catenin. Taken together, our findings strongly suggest that N-WASP plays a pivotal role in regulating HA-mediated CD44-ErbB2 interaction, -catenin signaling, and actin cytoskeleton functions that are required for tumor-specific behaviors and ovarian cancer progression.

Received for publication, May 16, 2006 , and in revised form, September 6, 2006.

^* This work was supported by United States Public Health Service Grants R01 CA66163, R01 CA 78633, and P01 AR39448, a Veterans Affairs merit review grant, and a Department of Defense grant. 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 and reprint requests should be addressed: Endocrine Unit (111N), Dept. of Medicine, University of California and Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-221-4810 (ext. 3321); Fax: 415-383-1638; E-mail: lilly.bourguignon{at}ucsf.edu.

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