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 Gi-coupled chemokine receptor CCR5, triggering its tyrosine phosphorylation and Galpha 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 KDELccr5A32 mutant abolishes IGF-I-induced migration. The relevance of this transactivation pathway was shown in vivo, as KDELccr5A32 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.
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificias, Universidad Autónoma de Madrid, Spain.
E
E
Mira
R A
RA
Lacalle
M A
MA
González
C
C
Gómez-Moutón
J L
JL
Abad
A
A
Bernad
C
C
Martínez-A
S
S
Mañes
D001943:Breast Neoplasms / Q000473:pathology; D016764:Cell Polarity / Q000187:drug effects; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008024:Ligands; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D021382:Protein Sorting Signals / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D018946:Chemokine CCL5; D008024:Ligands; D009842:Oligopeptides; D021382:Protein Sorting Signals; D012333:RNA, Messenger; D019713:Receptors, CCR5; C073762:lysyl-aspartyl-glutamyl-leucine; D007334:Insulin-Like Growth Factor I; D019206:GTP-Binding Protein alpha Subunits, Gi-Go