EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma.
Urokinase plasminogen activator receptor (uPAR) activates alpha5beta1 integrin and ERK signaling, inducing in vivo proliferation of HEp3 human carcinoma. Here we demonstrate that EGFR mediates the uPAR/integrin/fibronectin (FN) induced growth pathway. Its activation is ligand-independent and does not require high EGFR, but does require high uPAR expression. Only when uPAR level is constitutively elevated does EGFR become alpha5beta1-associated and activated. Domain 1 of uPAR is crucial for EGFR activation, and FAK links integrin and EGFR signaling. Inhibition of EGFR kinase blocks uPAR induced signal to ERK, implicating EGFR as an important effector of the pathway. Disruption of uPAR or EGFR signaling reduces HEp3 proliferation in vivo. These findings unveil a mechanism whereby uPAR subverts ligand-regulated EGFR signaling, providing cancer cells with proliferative advantage.
Department of Medicine, Division of Medical Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA.
David
D
Liu
Julio
J
Aguirre Ghiso
Yeriel
Y
Estrada
Liliana
L
Ossowski
D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011799:Quinazolines; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019012:Integrin beta1; C524898:PLAUR protein, human; D011799:Quinazolines; D011956:Receptors, Cell Surface; D017469:Receptors, Fibronectin; D055293:Receptors, Urokinase Plasminogen Activator; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases