QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 15, Issue 9, 4299-4309, September 2004

This Article Full Text Full Text (PDF) All Versions of this Article: E04-03-0233v1 15/9/4299    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kansra, S. Articles by Elder, J. T. Search for Related Content PubMed PubMed Citation Articles by Kansra, S. Articles by Elder, J. T.

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Sanjay Kansra ^*   , Stefan W. Stoll ^* , Jessica L. Johnson ^*, and James T. Elder ^*  || ¶

^* Departments of Dermatology, University of Michigan Medical Center, Ann Arbor, MI 48109; ^|| Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109; and ^¶ Ann Arbor Veterans Affairs Health System, Ann Arbor, MI 48105

Submitted March 18, 2004; Revised July 2, 2004; Accepted July 6, 2004
Monitoring Editor: Carl-Henrik Heldin

ErbB signaling through extracellular signal-regulated kinase (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 (NHKs) 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 epidermal growth factor (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 monoclonal antibody 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 NHKs, even when ErbB1 autophosphorylation and internalization are limited.

These authors made equal contributions to this study.

Present address: Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, 3125 Eden Ave., Cincinnati, OH 45267-0521.

Corresponding authors. E-mail addresses: jelder{at}umich.edu; sanjay.kansra{at}uc.edu.

This article has been cited by other articles:

				L. Rittie, S. Kansra, S. W. Stoll, Y. Li, J. E. Gudjonsson, Y. Shao, L. E. Michael, G. J. Fisher, T. M. Johnson, and J. T. Elder Differential ErbB1 Signaling in Squamous Cell versus Basal Cell Carcinoma of the Skin Am. J. Pathol., June 1, 2007; 170(6): 2089 - 2099. [Abstract] [Full Text] [PDF]

				K. Narita, J. Chien, S. A. Mullany, J. Staub, X. Qian, W. L. Lingle, and V. Shridhar Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer J. Biol. Chem., May 11, 2007; 282(19): 14413 - 14420. [Abstract] [Full Text] [PDF]

				D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]

				L. Lipfert, J. E. Fisher, N. Wei, A. Scafonas, Q. Su, J. Yudkovitz, F. Chen, S. Warrier, E. T. Birzin, S. Kim, et al. Antagonist-Induced, Activation Function-2-Independent Estrogen Receptor {alpha} Phosphorylation Mol. Endocrinol., March 1, 2006; 20(3): 516 - 533. [Abstract] [Full Text] [PDF]

				Y. Xu, L.-J. Tan, V. Grachtchouk, J. J. Voorhees, and G. J. Fisher Receptor-type Protein-tyrosine Phosphatase-{kappa} Regulates Epidermal Growth Factor Receptor Function J. Biol. Chem., December 30, 2005; 280(52): 42694 - 42700. [Abstract] [Full Text] [PDF]

				S. Kansra, S. W. Stoll, J. L. Johnson, and J. T. Elder Src Family Kinase Inhibitors Block Amphiregulin-Mediated Autocrine ErbB Signaling in Normal Human Keratinocytes Mol. Pharmacol., April 1, 2005; 67(4): 1145 - 1157. [Abstract] [Full Text] [PDF]