Mira E, Lacalle R A, González M A, Gómez-Moutón C, Abad J L, Bernad A, Martínez-A C, Mañes S
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificias, Universidad Autónoma de Madrid, Spain.
EMBO Rep. 2001 Feb;2(2):151-6. doi: 10.1093/embo-reports/kve027.
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.
复杂的细胞反应需要整合通过不同途径传递的信号。我们发现胰岛素样生长因子（IGF）-I可诱导与Gi偶联的趋化因子受体CCR5发生特异性反式激活，引发其酪氨酸磷酸化和Gα亚基募集。这种反式激活通过一种涉及RANTES（天然CCR5配体）转录上调和分泌的机制发生。CCR5反式激活是IGF-I诱导的细胞趋化作用中一个重要的下游信号，因为用反式显性负性KDELccr5A32突变体消除CCR5功能可消除IGF-I诱导的迁移。这种反式激活途径在体内的相关性得到了证实，因为KDELccr5A32过表达可阻止高转移性肿瘤细胞的侵袭；相反，RANTES过表达赋予非侵袭性肿瘤细胞系内在的侵袭能力。我们的结果表明，这种细胞外生长因子-趋化因子网络代表了一种连接肿瘤发生和炎症的一般机制。
