PAR-type thrombin receptors in renal carcinoma cells: PAR1-mediated EGFR activation promotes cell migration.
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.
Bergmann
Sebastian
S
Department of General, Friedrich Schiller University Jena, D-07747 Jena, Germany.
Junker
Kerstin
K
Henklein
Peter
P
Hollenberg
Morley D
MD
Settmacher
Utz
U
Kaufmann
Roland
R
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000503:physiopathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
D004151:Dipeptides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D009842:Oligopeptides; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D020032:Tyrphostins; C508781:threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine; C101044:RTKI cpd; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D013917:Thrombin; D020782:Matrix Metalloproteinases; D010975:Platelet Aggregation Inhibitors