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J. Biol. Chem., Vol. 281, Issue 20, 14085-14091, May 19, 2006

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An Interaction between Insulin-like Growth Factor-binding Protein 2 (IGFBP2) and Integrin 5 Is Essential for IGFBP2-induced Cell Mobility^*

George K. Wang, Limei Hu, Gregory N. Fuller, and Wei Zhang¹

From the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030

In the study we report here, we tested the hypothesis that insulin-like growth factor-binding protein 2 (IGFBP2) promotes cell mobility through its interaction with integrin 5. Our previous microarray studies showed that IGFBP2 activates the expression of integrin 5. In addition, IGFBP2 has an Arg-Gly-Asp (RGD) domain, which is a known integrin binding motif. We first confirmed our microarray results by showing that the expression of integrin 5 is indeed up-regulated at the protein level in IGFBP2-overexpressing SNB19 glioma cells. Using co-immunoprecipitation, we confirmed that IGFBP2 does interact with integrin 5. To confirm that IGFBP2 interacts directly with integrin 5 through the RGD domain, we created an RGD RGE mutant (D306E) IGFBP2 and stably overexpressed the mutant IGFBP2 in the same cell line. Co-immunoprecipitation then showed that D306E-IGFBP2 had no detectable binding with integrin 5. We further observed that IGFBP2-overexpressing cells have extensive cell surface lamellipodia, whereas D306E-IGFBP2-overexpressing cells show abundant cell surface focal adhesions. Consistent with this, phenotype analysis then showed that IGFBP2-overexpressing cells have elevated migration rates compared with vector control; in contrast, the migration rates of the D306E-IGFBP2-overexpressing cells were not elevated and were comparable with that of vector control. Decreased expression of integrin 5 by small interference RNA in IGFBP2-overexpressing cells also reduced cell mobility. Therefore, we have concluded that one mechanism by which IGFBP2 activates IGFBP2-induced cell mobility is through its interaction with integrin 5 and this interaction is specifically mediated through the RGD domain on IGFBP2.

Received for publication, December 23, 2005 , and in revised form, March 22, 2006.

^* This work was supported in part by National Institutes of Health Grant CA98503 (to W. Z. and G. N. F.), the Anthony Bullock III Research Fund (to W. Z. and G. N. F.), and Cancer Center Core Grant CA016672. 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 Pathology, Box 85, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-745-1103; Fax: 713–792-5549; E-mail: wzhang{at}mdanderson.org.

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