Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor.
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.
Fischer
Oliver M
OM
Department of Molecular Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
Hart
Stefan
S
Gschwind
Andreas
A
Prenzel
Norbert
N
Ullrich
Axel
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D019556:COS Cells; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D020868:Gene Silencing; D006493:Heparin / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009997:Osmotic Pressure; D018384:Oxidative Stress; D010766:Phosphorylation; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D004317:Doxorubicin; D006493:Heparin; D008666:Metalloendopeptidases