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J. Biol. Chem., Vol. 280, Issue 48, 39701-39708, December 2, 2005

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Transactivation of CXCR4 by the Insulin-like Growth Factor-1 Receptor (IGF-1R) in Human MDA-MB-231 Breast Cancer Epithelial Cells^*

From the School of Molecular and Biomedical Science, the University of Adelaide, Adelaide, South Australia, Australia, 5005

In the multimolecular environment in tissues and organs, cross-talk between growth factor and G protein-coupled receptors is likely to play an important role in both normal and pathological responses. In this report, we demonstrate transactivation of the chemokine receptor CXCR4 by the growth factor insulin-like growth factor (IGF)-1 is required for IGF-1-induced cell migration in metastatic MDA-MB-231 cells. The induction of chemotaxis in MDA-MB-231 cells by IGF-1 was inhibited by pretreatment of the cells with pertussis toxin (PTX) and by RNAi-mediated knockdown of CXCR4. Transactivation of the CXCR4 pathway by IGF-1 occurred independently of CXCL12, the chemokine ligand of CXCR4. Neither CXCR4 knockdown nor PTX had any effect on the ability of IGF-1 to activate IGF-1R, suggesting that CXCR4 and G proteins are activated subsequent to, or independently of, phosphorylation of IGF-1R by IGF-1. Coprecipitation studies revealed the presence of a constitutive complex containing IGF-1R, CXCR4, and the G protein subunits, G_i2 and G, and stimulation of MDA-MB-231 cells with IGF-1 led to the release of G_i2 and G from CXCR4. Based on our findings, we propose that CXCR4 constitutively forms a complex with IGF-1R in MDA-MB-231 cells, and that this interaction allows IGF-1 to activate migrational signaling pathways through CXCR4, G_i2 and G.

Received for publication, September 7, 2005

^* This work was supported by grants from the National Health & Medical Research Council of Australia. 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: Chemokine Biology, School of Molecular and Biomedical Science, the University of Adelaide, Adelaide, South Australia, Australia, 5005. Tel.: 618-8303-4259; Fax 618-8303-3337; E-mail: shaun.mccoll{at}adelaide.edu.au.

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