A role for chemokine receptor transactivation in growth factor signaling

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Abstract
Complex cell responses require the integration of signals delivered through different pathways. We show that insulin‐like growth factor (IGF)‐I induces specific transactivation of the Gi‐coupled chemokine receptor CCR5, triggering its tyrosine phosphorylation and Gαi recruitment. This transactivation occurs via a mechanism involving transcriptional upregulation and secretion of RANTES, the natural CCR5 ligand. CCR5 transactivation is an essential downstream signal in IGF‐I‐induced cell chemotaxis, as abrogation of CCR5 function with a transdominant‐negative KDELccr5Δ32 mutant abolishes IGF‐I‐induced migration. The relevance of this transactivation pathway was shown in vivo , as KDELccr5Δ32 overexpression prevents invasion by highly metastatic tumor cells; conversely, RANTES overexpression confers built‐in invasive capacity on a non‐invasive tumor cell line. Our results suggest that this extracellular growth factor‐chemokine network represents a general mechanism connecting tumorigenesis and inflammation.