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A more recent version of this article appeared on September 1, 2004
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Submitted on March 18, 2004
Revised on July 2, 2004
Accepted on July 6, 2004
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*Departments of Dermatology and ||Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109; and ¶Ann Arbor Veterans Affairs Health System, Ann Arbor, MI 48105
Monitoring Editor: Carl-Henrik Heldin
ErbB signaling through ERK has been implicated in regulating the expression of ErbB ligands in hyperproliferative skin disorders and wound healing. Here we characterize the process of autocrine ERK activation in cultured normal human keratinocytes (NHK) subjected to growth factor (GF) deprivation. Basal ERK phosphorylation was lower after 48 h than after 24 h of GF deprivation, and lowest at 30-60 min after an additional medium change. ERK phosphorylation was markedly increased by low concentrations of EGF (0.2 -1 ng/ml) that provoked only a limited increase in ErbB1 tyrosine phosphorylation and internalization. Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing mAb 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR). In contrast, these responses were unaffected by neutralizing antibodies against other ErbB1 ligands or the ErbB2 inhibitors geldanamycin and AG825. The time course of autocrine ERK phosphorylation correlated with the appearance of soluble AR, and two different metalloproteinase inhibitors blocked AR release. These results define an amphiregulin- and ErbB1-dependent mechanism by which autocrine ERK activation is maintained in NHK, even when ErbB1 autophosphorylation and internalization are limited.
These authors made equal contributions to the manuscript.
Present address: Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0521
Corresponding authors.
E-mail: Sanjay.Kansra{at}uc.edu E-mail: jelder{at}umich.edu
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