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A role for chemokine receptor transactivation in growth factor signaling
Author(s) -
Mira Emilia,
Lacalle Rosa Ana,
González Manuel A,
GómezMoutón Concepción,
Abad José Luis,
Bernad Antonio,
MartínezA Carlos,
Mañes Santos
Publication year - 2001
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kve027
Subject(s) - transactivation , microbiology and biotechnology , biology , cancer research , ccl21 , signal transduction , ccr1 , chemokine receptor , chemokine , inflammation , transcription factor , immunology , biochemistry , gene
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 Gα 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 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.