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J. Biol. Chem. 275 (26): 19803-19807

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Ligand Discrimination in Signaling through an ErbB4 Receptor Homodimer*

Colleen SweeneyDagger §, Cary Lai, David J. Riese II||, A. John DiamontiDagger , Lewis C. CantleyDagger , and Kermit L. Carraway IIIDagger

From the Dagger  Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, the  Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and the || Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907

The epidermal growth factor (EGF)-like family of growth factors elicits cellular responses by stimulating the dimerization, autophosphorylation, and tyrosine kinase activities of the ErbB family of receptor tyrosine kinases. Although several different EGF-like ligands are capable of binding to a single ErbB family member, it is generally thought that the biological and biochemical responses of a single receptor dimer to different ligands are indistinguishable. To test whether an ErbB receptor dimer is capable of discriminating among ligands we have examined the effect of four EGF-like growth factors on signaling through the ErbB4 receptor homodimer in CEM/HER4 cells, a transfected human T cell line ectopically expressing ErbB4 in an ErbB-null background. Despite stimulating similar levels of gross receptor tyrosine phosphorylation, the EGF-like growth factors betacellulin, neuregulin-1beta , neuregulin-2beta , and neuregulin-3 exhibited different biological potencies in a cellular growth assay. Moreover, the different ligands induced different patterns of recruitment of intracellular signaling proteins to the activated receptor and induced differential usage of intracellular kinase signaling cascades. Finally, two-dimensional phosphopeptide mapping of ligand-stimulated ErbB4 revealed that the different growth factors induce different patterns of receptor tyrosine phosphorylation. These results indicate that ErbB4 activation by growth factors is not generic and suggest that individual ErbB receptors can discriminate between different EGF-like ligands within the context of a single receptor dimer. More generally, our observations significantly modify our understanding of signaling through receptor tyrosine kinases and point to a number of possible models for ligand-mediated signal diversification.

* This work was supported by National Institutes of Health Grant CA71702 to (K. L. C.) and by a Massachusetts Department of Public Health Breast Cancer Research Program grant (to C. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, Harvard Inst. of Medicine, Rm. 1018, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-0934; Fax: 617-667-0957; E-mail:

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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