A role for chemokine receptor transactivation in growth factor signaling

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 G(i)-coupled chemokine receptor CCR5, triggering its tyrosine phosphorylation and G alpha (i) 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 ICF-I-induced cell chemotaxis, as abrogation of CCR5 function with a transdominant-negative KDELccr5 Delta 32 mutant abolishes IGF-I-induced migration. The relevance of this transactivation pathway was shown in vivo, as KDELccr5 Delta 32 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.