Transactivation of CXCR4 by IGF-1R in human MDA-MB-231 breast cancer epithelial cells

doi:10.1074/jbc.M509829200

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Transactivation of CXCR4 by IGF-1R in human MDA-MB-231 breast cancer epithelial cells

Chareeporn Akekawatchai, Jane D. Holland, Marina Kochetkova, John C. Wallace, and Shaun R. McColl

Molecular & Biomedical Science, Adelaide University, Adelaide 5005

Corresponding Author: shaun.mccoll{at}adelaide.edu.au

In the multi-molecular 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 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 pre-treatment 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, Gialpha2 and Gbeta, and stimulation of MDA-MB-231 cells with IGF-1 led to the release of Gialpha and Gbeta 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 signalling pathways through CXCR4, Gialpha2 and Gbeta.

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