Ligand discrimination in signaling through an ErbB4 receptor homodimer

Colleen A Sweeney, Cary Lai, David J. Riese, A. John Diamonti, Lewis C. Cantley, Kermit L Carraway

Research output: Contribution to journalArticle

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Abstract

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-1β, neuregulin-2β, 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.

Original languageEnglish (US)
Pages (from-to)19803-19807
Number of pages5
JournalJournal of Biological Chemistry
Volume275
Issue number26
DOIs
StatePublished - Jun 30 2000
Externally publishedYes

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Epidermal Growth Factor
Ligands
Intercellular Signaling Peptides and Proteins
Neuregulins
Dimers
Phosphorylation
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
Intracellular Signaling Peptides and Proteins
Neuregulin-1
Phosphopeptides
T-cells
Dimerization
Assays
Phosphotransferases
Chemical activation
T-Lymphocytes
Cell Line
Growth
ErbB Receptors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ligand discrimination in signaling through an ErbB4 receptor homodimer. / Sweeney, Colleen A; Lai, Cary; Riese, David J.; Diamonti, A. John; Cantley, Lewis C.; Carraway, Kermit L.

In: Journal of Biological Chemistry, Vol. 275, No. 26, 30.06.2000, p. 19803-19807.

Research output: Contribution to journalArticle

Sweeney, Colleen A ; Lai, Cary ; Riese, David J. ; Diamonti, A. John ; Cantley, Lewis C. ; Carraway, Kermit L. / Ligand discrimination in signaling through an ErbB4 receptor homodimer. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 26. pp. 19803-19807.
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