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Originally published In Press as doi:10.1074/jbc.M210877200 on November 7, 2002

J. Biol. Chem., Vol. 278, Issue 3, 1642-1646, January 17, 2003
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Epidermal Growth Factor Receptor-dependent and -independent Cell-signaling Pathways Originating from the Urokinase Receptor*

Minji Jo, Keena S. Thomas, Denise M. O'Donnell, and Steven L. GoniasDagger

From the Departments of Pathology, Biochemistry, and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Urokinase-type plasminogen activator (uPA) and vitronectin activate cell-signaling pathways by binding to the uPA receptor (uPAR). Because uPAR is glycosylphosphatidylinositol-anchored, the signaling receptor is most likely a uPAR-containing multiprotein complex. This complex may be heterogeneous within a single cell and among different cell types. The goal of this study was to elucidate the role of the EGF receptor (EGFR) as a component of the uPAR-signaling machinery. uPA activated extracellular signal-regulated kinase (ERK) in COS-7 cells and in COS-7 cells that overexpress uPAR, and this response was blocked by the EGFR inhibitor, tyrphostin AG1478, implicating the EGFR in the pathway that links uPAR to ERK. By contrast, Rac1 activation, which occurred as a result of uPAR overexpression, was EGFR-independent. COS-7 cell migration was stimulated, in an additive manner, by uPAR-dependent pathways leading to ERK and Rac1. AG1478 inhibited only the ERK-dependent component of the response. CHO-K1 cells do not express EGFR; however, these cells demonstrated ERK activation in response to uPA, indicating the presence of an EGFR-independent alternative pathway. As anticipated, this response was insensitive to AG1478. When CHO-K1 cells were transfected to express EGFR or a kinase-inactive mutant of EGFR, ERK activation in response to uPA was unchanged; however, the EGFR-expressing cells acquired sensitivity to AG1478. We conclude that the EGFR may function as a transducer of the signal from uPAR to ERK, but not Rac1. In the absence of EGFR, an alternative pathway links uPAR to ERK; however, this pathway is apparently silenced by EGFR expression.

* This work was supported by Grant R01 CA94900 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Depts. of Pathology, Biochemistry, and Molecular Genetics, Box 800214, Charlottesville, VA 22908; Tel.: 434-924-9192; Fax: 434-982-0283; E-mail: slg2t@virginia.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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