Journal
PHARMACOLOGY & THERAPEUTICS
Volume 122, Issue 1, Pages 1-8Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2008.11.008
Keywords
Epidermal growth factor receptor; EGF; ErbB receptors; ErbB4; Signal transduction; Neuregulins; Transforming growth factor alpha; Amphiregulin
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Funding
- National Institutes of Health [AR045585, DK067875, CA080770, CA114209]
- United States Army Medical Research and Materiel Command Breast Cancer Research Program [DAMD-17-00-1-0416]
- Susan G. Komen for the Cure
- NATIONAL CANCER INSTITUTE [R01CA114209, R01CA079992, R21CA080770] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR045585] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R21DK067875] Funding Source: NIH RePORTER
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Breast, prostate, pancreatic, colorectal, lung, and head and neck cancers exploit deregulated signaling by ErbB family receptors and their ligands, EGF family peptide growth factors. EGF family members that bind the same receptor are able to stimulate divergent biological responses both in cell culture and in vivo. This is analogous to the functional selectivity exhibited by ligands for G-protein coupled receptors. Here we review this literature and propose that this functional selectivity of EGF family members is due to distinctions in the conformation of the liganded receptor and subsequent differences in the sites of receptor tyrosine phosphorylation and receptor coupling to signaling effectors. We also discuss the roles of divergent ligand activity in establishing and maintaining malignant phenotypes. Finally, we discuss the potential of mutant EGF family ligands as cancer chemotherapeutics targeted to ErbB receptors. (C) 2008 Elsevier Inc. All rights reserved.
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