Identification of G protein-coupled receptors potently stimulating migration of human transitional-cell carcinoma cells

Lümmen, G.; Virchow, Sebastian; Rümenapp, Ulrich; Schmidt, Martina; Wieland, Thomas; Otto, T.; Rübben, H.; Jakobs, Karl H.

doi:10.1007/pl00005117

Cited by 39 publications

(51 citation statements)

References 35 publications

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“…For example, it was shown that AR triggers proliferation and TGFa induces invasion in cell lines derived from invasive transitional cancer tissue (De Boer et al, 1997). Little is known, however, about the function of GPCRs relating to bladder and kidney cancer with modest EGFR levels, although human transitional carcinoma cells express various GPCRs and display an enhanced migration rate in response to LPA and thrombin (Lummen et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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

2003

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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.

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Section: Discussionmentioning

confidence: 99%

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

2003

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“…Whatever the precise mechanism, the pathway also is likely to be important in other aspects of fibroblast migration and chemotaxis (47,48). This pathway clearly differs from routine cell spreading and stress fiber formation, however, because fibroblasts were able to spread and form stress fibers on proteincoated surfaces under conditions that matrix contraction did not occur (e.g.…”

Section: Discussionmentioning

confidence: 99%

Increased Myosin Light Chain Phosphorylation Is Not Required for Growth Factor Stimulation of Collagen Matrix Contraction

Skuta¹,

Grinnell

1999

Journal of Biological Chemistry

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Previous research suggested the possibility that contraction of floating collagen matrices by human fibroblasts required increased myosin light chain (MLC) phosphorylation. In the current studies, we show that increased MLC phosphorylation was neither necessary for platelet-derived growth factor (PDGF)-dependent matrix contraction nor sufficient for lysophosphatidic acid (LPA)-dependent contraction. In contrast, increased MLC phosphorylation did appear to be coupled to the formation of stress fibers by cells spreading in monolayer culture. Signal transduction pathways required for PDGF-and LPA-dependent matrix contraction involved phosphatidylinositol 3-kinase and the G i class of heterotrimeric G proteins, respectively. Our results indicate that PDGF-and LPA-dependent contraction of floating collagen matrices can be uncoupled from an increase in MLC phosphorylation.

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“…LPA stimulation of fibroblast migration and chemotaxis was shown to depend on LPA receptors coupled to G i (44,45). On the other hand, LPA stimulation of stress fiber formation and focal adhesion assembly requires activation of the small G-protein Rho (29,30), a pertussis toxin-insensitive process (31) in which LPA receptors are coupled to G 13 (32).…”

Section: Discussionmentioning

confidence: 99%

Differences in the Regulation of Fibroblast Contraction of Floating Versus Stressed Collagen Matrices

Grinnell

Lin

et al. 1999

Journal of Biological Chemistry

170

152

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To learn more about the regulation of contraction of collagen matrices by fibroblasts, we compared the ability of lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) to stimulate contraction of floating and stressed collagen matrices. In floating collagen matrices, PDGF and LPA stimulated contraction with similar kinetics, but appeared to utilize complementary signaling pathways since contraction obtained by the combination of growth factors exceeded that observed with saturating concentrations of either alone. The PDGF-simulated pathway was selectively inhibited by the protein kinase inhibitor KT5926. In stressed collagen matrices, PDGF and LPA stimulated contraction with different kinetics, with LPA acting rapidly and PDGF acting only after an ϳ1-h lag period. Pertussis toxin, known to block signaling through the G i class of heterotrimeric G-proteins, inhibited LPA-stimulated contraction of floating but not stressed matrices, suggesting that LPA-stimulated contraction depends on receptors coupled to different G-proteins in floating and stressed matrices. On the other hand, the Rho inhibitor C3 exotransferase blocked contraction of both floating and stressed collagen matrices. These results suggest the possibility that distinct signaling mechanisms regulate contraction of floating and stressed collagen matrices.Closure of cutaneous wounds involves three processes: epithelialization, connective tissue deposition, and contraction. Wound contraction, which brings the margins of open wounds together (1, 2), is believed to be mediated by specialized fibroblasts called myofibroblasts because of their content of actin stress fibers and ␣-smooth muscle actin (3). The myofibroblast phenotype can occur early or late during the wound contraction process depending on the mechanical resistance of surrounding tissue (4). Myofibroblasts have also been implicated in the pathology of wound contractures and fibrotic disease (5, 6).Using several different culture models, we and others have studied the ability of fibroblasts to reorganize and contract collagen matrices in vitro. In the "floating" model (7), a freshly polymerized collagen matrix containing fibroblasts is released from the culture dish and allowed to float in culture medium, and contraction occurs in the absence of external mechanical load and without appearance of actin stress fibers in the cells (8). In the "attached" model, a polymerized collagen matrix containing fibroblasts remains attached to the culture dish during contraction. In this case, mechanical load (i.e. isometric tension) develops during contraction, and cellular stress fibers assemble (9 -11). Finally, the two-step "stressed" model combines an initial period of attached matrix contraction leading to mechanical loading, followed by release of the matrices, resulting in mechanical unloading and further contraction as mechanical stress dissipates (i.e. stress-relaxation) (12).Contraction of collagen matrices depends on cell binding to collagen through ␣ 2 ␤ 1 integrins (13-15) and r...

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Identification of G protein-coupled receptors potently stimulating migration of human transitional-cell carcinoma cells

Cited by 39 publications

References 35 publications

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

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

Increased Myosin Light Chain Phosphorylation Is Not Required for Growth Factor Stimulation of Collagen Matrix Contraction

Differences in the Regulation of Fibroblast Contraction of Floating Versus Stressed Collagen Matrices

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