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 induce s specific transactivation of the G(i)-coupled chemokine receptor CCR5, tri ggering its tyrosine phosphorylation and G alpha (i) recruitment. This tran sactivation occurs via a mechanism involving transcriptional upregulation a nd secretion of RANTES, the natural CCR5 ligand. CCR5 transactivation is an essential downstream signal in ICF-I-induced cell chemotaxis, as abrogatio n of CCR5 function with a transdominant-negative KDELccr5 Delta 32 mutant a bolishes IGF-I-induced migration. The relevance of this transactivation pat hway was shown in vivo, as KDELccr5 Delta 32 overexpression prevents invasi on by highly metastatic tumor cells; conversely, RANTES overexpression conf ers built-in invasive capacity on a non-invasive tumor cell line. Our resul ts suggest that this extracellular growth factor-chemokine network represen ts a general mechanism connecting tumorigenesis and inflammation.