TY - JOUR
T1 - EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma
AU - Liu, David
AU - Aguirre Ghiso, Julio A.
AU - Estrada, Yeriel
AU - Ossowski, Liliana
N1 - Funding Information:
We thank Drs. Rafael Mira y Lopez and George Acs for critical reading of the manuscript, Dr. Inigo Santamaria Ruiz de Azua for preparation of the uPAR-mutant expression vectors, and Dr. Samuel Waxman for continuous encouragement and support. We gratefully acknowledge the gift of the following reagents: monoclonal anti-uPAR antibody (R2) from Dr. Michael Ploug (Finsen Laboratory, Copenhagen DK); rat monoclonal anti α5β1 antibody (AIIB2) from Dr. Caroline Damsky (University of California, San Francisco, CA); CD533 from Dr. Axel Ullrich (Max Planck Institute, Germany); single chain uPA from Dr. Jack Henkin (Abbott Laboratories, Abbot Park, IL); TGF-α primers and rabbit polyclonal anti-EGFR antibody from Dr. Paolo Fedi (Mount Sinai School of Medicine, New York, NY); amphiregulin DNA and primers from Dr. Jonathan Licht. Confocal laser scanning microscopy was supported with funding from the National Science Foundation Major Research Instrumentation Grant (DBI9724504) of the Mount Sinai School of Medicine Microscopy Center. This work was supported by U.S. Public Health Service Research Grant (CA-40758) (L.O.), NIH/MSSM Medical Scientist Training Program and NCI predoctoral training grant (CA78207) (D.L.), The Charles H. Revson Foundation (J.A.A.G.) and The Samuel Waxman Cancer Research Foundation.
PY - 2002/6
Y1 - 2002/6
N2 - Urokinase plasminogen activator receptor (uPAR) activates α5β1 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 α5β1-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.
AB - Urokinase plasminogen activator receptor (uPAR) activates α5β1 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 α5β1-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.
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U2 - 10.1016/S1535-6108(02)00072-7
DO - 10.1016/S1535-6108(02)00072-7
M3 - Article
C2 - 12124174
AN - SCOPUS:0036596352
SN - 1535-6108
VL - 1
SP - 445
EP - 457
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -