Urokinase Receptor Is Associated with the Components of the JAK1/STAT1 Signaling Pathway and Leads to Activation of This Pathway upon Receptor Clustering in the Human Kidney Epithelial Tumor Cell Line TCL-598*
- From the ‡Department of Vascular Biology and Thrombosis Research, University of Vienna, A-1090 Vienna, Austria and the §Institute of Biochemistry, RWTH Aachen, Germany
Abstract
The urokinase-type plasminogen activator (uPA) binds to cells via a specific receptor attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Despite the lack of a transmembrane domain, the urokinase receptor (uPAR) is capable of transducing extracellular signals affecting growth, migration, and adhesion. Several Tyr kinases of the src family as well as β1, β2, and β3 integrins were found to be associated with the uPAR. We found that in the human kidney epithelial line TCL-598, also components of the JAK1/STAT1 signal transduction pathway including gp130, are associated with uPAR as revealed by coimmunoprecipitation and are co-localized in caveolae. Upon clustering of uPA·uPAR complex by a monoclonal antibody, JAK1 associates with uPAR, which in turn leads to STAT1 phosphorylation, dimerization, specific binding to DNA, and gene activation. To prove the dependence of STAT1 activation on the uPAR, TCL-598 cells were treated with sense and antisense uPAR oligonucleotides. In antisense-treated cells in which uPAR expression was reduced to less then one third, activation of STAT1 by the clustering antibody was abolished while STAT1 activation by interferon-γ was unaffected. Therefore, in this cell line, uPA·uPAR also utilizes the JAK1/STAT1 pathway for signaling, and gp130 might be the transmembrane adapter for this signal transduction pathway.
Footnotes
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↵* This work was supported by Grants F509 and 10049 from the Austrian Fund for the Promotion of Scientific Research.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.
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↵¶ To whom correspondence should be addressed: Dept. of Vascular Biology and Thrombosis Research, University of Vienna, Schwarzspanierstrasse 17, A-1090 Vienna, Austria. Tel.: 43-1-40480 230; Fax: 43-1-4087500; E-mail:bernd.binder{at}univie.ac.at.
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↵1 The abbreviations used are: uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor; GPI, glycosylphosphatidylinositol; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor; PMSF, phenylmethylsulfonyl fluoride; DTT, dithiotreitol; MES, 2-(N-morpholino)ethanesulfonic acid; DSS, disuccinimidyl suberate; IFN-γ, interferon-γ; IL, interleukin; PBS, phosphate-buffered saline.
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- Received December 12, 1996.
- Revision received September 4, 1997.
