Abstract
Cross-talk between G-protein-coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signaling systems is established in a wide variety of normal and neoplastic cell types. Here, we show that proteinase-activated receptor 1 (PAR1) mediates the tyrosine phosphorylation of EGFR in human renal carcinoma cells expressing PAR1 and PAR3 endogeneously. This GPCR-EGFR signal transduction pathway cross-talk requires matrix metalloproteinase activity and is involved in the regulation of renal carcinoma cell migration across a collagen barrier as shown using a Boyden chamber type assay. Our data therefore document a regulatory role of PAR1-mediated EGFR transactivation in cancer cell chemotactic migration. Further, our results underline the importance of PAR1-mediated pathways in kidney cancer cells and suggest that the thrombin/PAR1 system mediating EGFR transactivation may play a role in the progression of this tumor entity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / physiology*
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Dipeptides / pharmacology
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / metabolism*
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Humans
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Kidney Neoplasms / pathology
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Kidney Neoplasms / physiopathology
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / metabolism
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Oligopeptides / pharmacology
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Phosphorylation / drug effects
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Pyrroles / pharmacology
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Quinazolines / pharmacology
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Receptor, PAR-1 / agonists
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Receptor, PAR-1 / antagonists & inhibitors
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Receptor, PAR-1 / physiology*
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Thrombin / pharmacology
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Tyrosine / metabolism
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Tyrphostins / pharmacology
Substances
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Dipeptides
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Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
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N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
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Oligopeptides
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Pyrroles
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Quinazolines
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Receptor, PAR-1
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Tyrphostins
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threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine
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RTKI cpd
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Tyrosine
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Epidermal Growth Factor
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ErbB Receptors
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Thrombin
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Matrix Metalloproteinases