Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion

Abstract

Signalling through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) is involved in the regulation of essential cellular processes and its deregulation is associated with tumorigenesis in vitro and in vivo. We investigated pathophysiological processes that are regulated by GPCR pathways in human kidney and bladder cancer cell lines. Our results show that GPCR ligands induce tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) as well as downstream signalling events such as recruitment of the adapter protein Shc and activation of the mitogen-activated protein kinases (MAPK) ERK1/2, JNK and p38. Moreover, we report that the EGFR transactivation signal involves the EGFR ligands amphiregulin, HB-EGF and TGFa as well as the metalloproteinases ADAM 10, 15 and 17, depending on the cellular system. Finally, we demonstrate that EGFR transactivation is part of a regulatory system that modulates the migratory and invasive behaviour of kidney and bladder cancer cells. In conclusion, our findings demonstrate that metalloproteinase-mediated transactivation of the EGFR is a key mechanism of the cellular signalling network that promotes MAPK activation as well as tumour cell migration and invasion in response to a variety of physiologically relevant GPCR ligands, and therefore represents a novel target for cancer intervention strategies.

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

“…The observation that the wound repair can be rescued with the addition of HB-EGF indicates that migration depends on the availability and/or release of HB-EGF into the medium. These data support our hypothesis that the purinergic receptors are one member of the family of GPCRs that are hypothesized to participate in the cross talk with EGFR via release of HB-EGF (Schafer et al 2004a).…”

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

“…In this area, RhoGTPases play pleiotropic roles in cell movements, polarity, vesicle trafficking, and EGF-R processing and degradation, as recently demonstrated for Cdc42 (Cerione, 2004). GPCR controlled by thrombin, bombesin, neurotensin, endothelin, and LPA are also implicated in metalloprotease-mediated EGF-R transactivation (Darmoul et al, 2004;Schafer et al, 2004;Zhao et al, 2004), a major signaling platform in invasive growth (Rodrigues et al, 2003). More recently, the fibroblast-derived matrix metalloprotease MMP-1 in the stromal-tumor microenvironment has been designed as a new PAR-1 activator that promotes invasion and tumorigenesis of breast cancer cells (Boire et al, 2005).…”

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

“…But whereas only one EGFR ligand (AREG) appears to be expressed in the right abundance, place and time during post-pubertal mammary development, several ADAMs are expressed at this stage, at least two of which (ADAMs 15 and 17) can process AREG [64]. Nevertheless, only ADAM17 appears to be required, as other ADAMs are unable to compensate for its absence and since triple-null mice lacking ADAMs 9, 12 and 15 are fully able to nurse their pups (C. Blobel, personal communication).…”