Growth Factor-specific Signaling Pathway Stimulation and Gene Expression Mediated by ErbB Receptors

Colleen A Sweeney, Douglas Fambrough, Christine Huard, A. John Diamonti, Eric S. Lander, Lewis C. Cantley, Kermit L Carraway

Research output: Contribution to journalArticle

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Abstract

The mechanisms by which receptor tyrosine kinases (RTKs) utilize intracellular signaling pathways to direct gene expression and cellular response remain unclear. A current question is whether different RTKs within a single cell target similar or different sets of genes. In this study we have used the ErbB receptor network to explore the relationship between RTK activation and gene expression. We profiled growth factor-stimulated signaling pathway usage and broad gene expression patterns in two human mammary tumor cell lines expressing different complements of ErbB receptors. Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1β acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt. The two growth factors regulated partially overlapping yet distinct sets of genes in these cells. In MDA-MB-453 cells, NRG2β acting through an ErbB2/ErbB3 heterodimer stimulated prolonged signaling of all pathways examined relative to NRG2β acting through the same heterodimeric receptor species. Surprisingly, NRG1β and NRG2β also regulated partially overlapping but distinct sets of genes in these cells. These results demonstrate that the activation of different RTKs, or activation of the same RTKs with different ligands, can lead to distinct profiles of gene regulation within a single cell type. Our observations also suggest that the identity and kinetics of signaling pathway usage by RTKs may play a role in the selection of regulated genes.

Original languageEnglish (US)
Pages (from-to)22685-22698
Number of pages14
JournalJournal of Biological Chemistry
Volume276
Issue number25
DOIs
StatePublished - Jun 22 2001

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Receptor Protein-Tyrosine Kinases
Gene expression
Intercellular Signaling Peptides and Proteins
Gene Expression
Genes
Chemical activation
Epidermal Growth Factor
Neuregulin-1
Complement Receptors
Tumor Cell Line
Epidermal Growth Factor Receptor
Protein Kinase C
ErbB Receptors
Tumors
Cells
Breast Neoplasms
Ligands
Kinetics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Growth Factor-specific Signaling Pathway Stimulation and Gene Expression Mediated by ErbB Receptors. / Sweeney, Colleen A; Fambrough, Douglas; Huard, Christine; Diamonti, A. John; Lander, Eric S.; Cantley, Lewis C.; Carraway, Kermit L.

In: Journal of Biological Chemistry, Vol. 276, No. 25, 22.06.2001, p. 22685-22698.

Research output: Contribution to journalArticle

Sweeney, Colleen A ; Fambrough, Douglas ; Huard, Christine ; Diamonti, A. John ; Lander, Eric S. ; Cantley, Lewis C. ; Carraway, Kermit L. / Growth Factor-specific Signaling Pathway Stimulation and Gene Expression Mediated by ErbB Receptors. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 25. pp. 22685-22698.
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