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Am J Physiol Gastrointest Liver Physiol (March 3, 2005). doi:10.1152/ajpgi.00280.2004
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Submitted on June 30, 2004
Accepted on February 21, 2005

Extracellular Cysteine/Cystine Redox Regulates the p44/42 MAPK Pathway by Metalloproteinase-dependent Epidermal Growth Factor Receptor (EGFR) Signaling

Yvonne S. Nkabyo1, Young-Mi Go2, Thomas R. Ziegler2, and Dean P. Jones3*

1 Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA
2 Department of Medicine, Emory University, Atlanta, GA, USA
3 Department of Medicine and the Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA

* To whom correspondence should be addressed. E-mail: dpjones{at}emory.edu.

Previous research shows that stimulation of proliferation of colon carcinoma (Caco-2) cells by a more reduced extracellular cysteine/cystine (Cys/CySS) redox state occurs with no apparent effect on intracellular glutathione (GSH), and that this stimulation is lost upon addition of epidermal growth factor (EGF). The purpose of the present study was to determine whether a more reduced extracellular Cys/CySS redox state activates the mitogenic p44/42 MAPK pathway and whether this is signaled through the EGF receptor (EGFR). Caco-2 cells were exposed to a range of physiologic extracellular redox conditions from -150 to 0 mV. In the absence of added growth factors, the most reduced (-150 mV) redox state induced an 80% increase in EGFR phosphorylation, and this was followed by a marked increase in phosphorylation of p44/42 MAPK. Inhibitors of EGFR (AG1478) and p44/42 MAPK (U0126) phosphorylation blocked redox-dependent p44/42 phosphorylation, indicating that signaling occurred by EGFR. These effects were inhibited by pretreatment with a non-permeant alkylating agent, showing that signaling involved thiols accessible to the extracellular space. The EGFR ligand TGF{alpha} was increased in culture medium at more reduced redox states. Redox-dependent phosphorylation of EGFR was completely prevented by a metalloproteinase inhibitor (GM6001), and an antibody to TGF{alpha} partially inhibited the phosphorylation of p44/42 MAPK by redox. Thus, the data show that a redox-dependent activation of metalloproteinase can stimulate the mitogenic p44/42 MAPK pathway by a TGF{alpha}-dependent mechanism. Because Cys availability and Cys/CySS redox are dependent upon nutrition, disease and environmental exposures, the results suggest that cell proliferation could be influenced physiologically by Cys-dependent redox effects on growth factor signaling pathways.




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