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J. Biol. Chem., Vol. 282, Issue 18, 13303-13315, May 4, 2007

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Consequences of Direct Versus Indirect Activation of Epidermal Growth Factor Receptor in Intestinal Epithelial Cells Are Dictated by Protein-tyrosine Phosphatase 1B^*

From the Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093

The epidermal growth factor receptor (EGFR) is an integral regulator of many cellular functions. EGFR also acts as a central conduit for extracellular signals involving direct activation of the receptor by EGFR ligands or indirect activation by G protein-coupled receptor (GPCR)-stimulated transactivation of the EGFR. We have previously shown that EGFR negatively regulates epithelial chloride secretion as a result of transforming growth factor--mediated EGFR transactivation in response to muscarinic GPCR activation. Here we show that direct activation of the EGFR by EGFR ligands produces a different pattern of EGFR tyrosine phosphorylation and downstream phosphatidylinositol 3-kinase recruitment than GPCR-stimulated transactivation of the EGFR occurring via paracrine EGFR ligand release. Moreover, we demonstrate that this differential signaling and its consequences depend on protein-tyrosine phosphatase 1B activity. Thus protein-tyrosine phosphatase 1B governs differential recruitment of signaling pathways involved in EGFR regulation of epithelial ion transport. Our findings furthermore establish how divergent signaling outcomes can arise from the activation of a single receptor.

Received for publication, January 16, 2007 , and in revised form, February 28, 2007.

^* This research was funded by a Crohn and Colitis Research Fellowship Award (to D. F. M.) and National Institutes of Health Grant DK28305 (to K. E. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Gastroenterology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0063. Tel.: 858-534-2794; Fax: 858-534-3338; E-mail: dmccole{at}ucsd.edu.

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