Journal of Biological Chemistry
Volume 276, Issue 52, 28 December 2001, Pages 48679-48692
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MECHANISMS OF SIGNAL TRANSDUCTION
Hyaluronan Promotes CD44v3-Vav2 Interaction with Grb2-p185HER2 and Induces Rac1 and Ras Signaling during Ovarian Tumor Cell Migration and Growth*

https://doi.org/10.1074/jbc.M106759200Get rights and content
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In this study we initially examined the interaction between CD44v3 (a hyaluronan (HA) receptor) and Vav2 (a guanine nucleotide exchange factor) in human ovarian tumor cells (SK-OV-3.ipl cell line). Immunological data indicate that both CD44v3 and Vav2 are expressed in SK-OV-3.ipl cells and that these two proteins are physically linked as a complex in vivo. By using recombinant fragments of Vav2 and in vitro binding assays, we have detected a specific binding interaction between the SH3-SH2-SH3 domain of Vav2 and the cytoplasmic domain of CD44. In addition, we have observed that the binding of HA to CD44v3 activates Vav2-mediated Rac1 signaling leading to ovarian tumor cell migration. Further analyses indicate that the adaptor molecule, growth factor receptor-bound protein 2 (Grb2) that is bound to p185HER2 (an oncogene product), is also associated with the CD44v3-Vav2 complex. HA binding to SK-OV-3.ipl cells promotes recruitment of both Grb2 and p185HER2 to the CD44v3-Vav2 complex leading to Ras activation and ovarian tumor cell growth. In order to determine the role of Grb2 in CD44v3 signaling, we have transfected SK-OV-3.ipl cells with Grb2 mutant cDNAs (e.g. ΔN-Grb2 that has a deletion in the amino-terminal SH3 domain or ΔC-Grb2 that has a deletion in the carboxyl-terminal SH3 domain). Our results clearly indicate that the SH3 domain deletion mutants of Grb2 (i.e. the ΔN-Grb2 (and to a lesser extent the ΔC-Grb2) mutant) not only block their association with p185HER2 but also significantly impair their binding to the CD44v3-Vav2 complex and inhibit HA/CD44v3-induced ovarian tumor cell behaviors. Taken together, these findings strongly suggest that the interaction of CD44v3-Vav2 with Grb2-p185HER2 plays an important role in the co-activation of both Rac1 and Ras signaling that is required for HA-mediated human ovarian tumor progression.

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Published, JBC Papers in Press, October 17, 2001, DOI 10.1074/jbc.M106759200

*

This work was supported in part by United States Public Health Grants CA66163 and CA 78633, Department of Defense Grants DAMD 17-97-1-7014 and DAMD 17-99-1-9291, and the generous donation from the late Dennece Mason.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a research fellowship from the Deutsche Forschungsgemeinschaft.

**

Supported by American Heart Association predoctoral fellowship.