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Molecular and Cellular Biology, June 2004, p. 5172-5183, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5172-5183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Oxidative and Osmotic Stress Signaling in Tumor Cells Is Mediated by ADAM Proteases and Heparin-Binding Epidermal Growth Factor

Oliver M. Fischer, Stefan Hart, Andreas Gschwind,{dagger} Norbert Prenzel,{ddagger} and Axel Ullrich*

Department of Molecular Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

Received 28 October 2003/ Returned for modification 8 January 2004/ Accepted 6 March 2004

Mammalian cells respond to environmental stress by activating a variety of protein kinases critical for cellular signal transmission, such as the epidermal growth factor receptor (EGFR) tyrosine kinase and different members of the mitogen-activated protein kinase (MAPK) family. EGFR activation by stress stimuli was previously thought to occur independently of stimulation by extracellular ligands. Here, we provide evidence that osmotic and oxidative stresses induce a metalloprotease activity leading to cell surface cleavage of pro-heparin-binding EGF (pro-HB-EGF) and subsequent EGFR activation. This ligand-dependent EGFR signal resulted from stress-induced activation of the MAPK p38 in human carcinoma cells and was mediated by the metalloproteases ADAM9, -10, and -17. Furthermore, stress-induced EGFR activation induced downstream signaling through the MAPKs extracellular signal-regulated kinases 1 and 2 and JNK. Interestingly, apoptosis induced by treatment of tumor cells with doxorubicin was strongly enhanced by blocking HB-EGF function. Together, our data provide novel insights into the mammalian stress response, suggesting a broad mechanistic relevance of a p38-ADAM-HB-EGF-EGFR-dependent pathway and its potential significance for tumor cells in evasion of chemotherapeutic agent-induced apoptosis.

* Corresponding author. Mailing address: Department of Molecular Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18A, D-82152 Martinsried, Germany. Phone: 49-89-8578-2512. Fax: 49-89-8578-2454. E-mail: ullrich{at}biochem.mpg.de.

{dagger} Present address: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.

{ddagger} Present address: U3 Pharma AG, 82152 Martinsried, Germany.

Molecular and Cellular Biology, June 2004, p. 5172-5183, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5172-5183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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