The erbB-2 Mitogenic Signaling Pathway

Tyrosine Phosphorylation of Phospholipase C-γ and GTPase-Activating Protein Does Not Correlate with erbB-2 Mitogenic Potency

Francesca Fazioli, Uh Hyun Kim, Sue Goo Rhee, Christopher J. Molloy, Oreste Segatto, Pier Paolo Di Fiore

Research output: Contribution to journalArticle

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Abstract

The erbB-2 gene product, gp185erbB-2, unlike the structurally related epidermal growth factor (EGF) receptor (EGFR), exhibits constitutive kinase and transforming activity. We used a chimeric EGFR/erbB-2 expression vector to compare the mitogenic signaling pathway of the erbB-2 kinase with that of the EGFR, at similar levels of expression, in response to EGF stimulation. The EGFR/erbB-2 chimera was significantly more active in inducing DNA synthesis than the EGFR when either was expressed in NIH 3T3 cells. Analysis of biochemical pathways implicated in signal transduction by growth factor receptors indicated that both phospholipase C type γ (PLC-γ) and the p21ras GTPase-activating protein (GAP) are substrates for the erbB-2 kinase in NIH 3T3 fibroblasts. However, under conditions in which activation of the erbB-2 kinase induced DNA synthesis at least fivefold more efficiently than the EGFR, the levels of erbB-2- or EGFR-induced tyrosine phosphorylation of PLC-γ and GAP were comparable. In addition, the stoichiometry of tyrosine phosphorylation of these putative substrates by erbB-2 appeared to be at least an order of magnitude lower than that induced by platelet-derived growth factor receptors at comparable levels of mitogenic potency. Thus, our results indicate that differences in tyrosine phosphorylation of PLC-γ and GAP do not account for the differences in mitogenic activity of the erbB-2 kinase compared with either the EGFR or platelet-derived growth factor receptor in NIH 3T3 fibroblasts.

Original languageEnglish
Pages (from-to)2040-2048
Number of pages9
JournalMolecular and Cellular Biology
Volume11
Issue number4
Publication statusPublished - Apr 1991

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GTPase-Activating Proteins
Type C Phospholipases
Epidermal Growth Factor Receptor
Tyrosine
Phosphorylation
Phosphotransferases
Platelet-Derived Growth Factor Receptors
Fibroblasts
Polynucleotide 5'-Hydroxyl-Kinase
erbB-2 Genes
NIH 3T3 Cells
Growth Factor Receptors
Epidermal Growth Factor
Signal Transduction
DNA

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

The erbB-2 Mitogenic Signaling Pathway : Tyrosine Phosphorylation of Phospholipase C-γ and GTPase-Activating Protein Does Not Correlate with erbB-2 Mitogenic Potency. / Fazioli, Francesca; Kim, Uh Hyun; Rhee, Sue Goo; Molloy, Christopher J.; Segatto, Oreste; Di Fiore, Pier Paolo.

In: Molecular and Cellular Biology, Vol. 11, No. 4, 04.1991, p. 2040-2048.

Research output: Contribution to journalArticle

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abstract = "The erbB-2 gene product, gp185erbB-2, unlike the structurally related epidermal growth factor (EGF) receptor (EGFR), exhibits constitutive kinase and transforming activity. We used a chimeric EGFR/erbB-2 expression vector to compare the mitogenic signaling pathway of the erbB-2 kinase with that of the EGFR, at similar levels of expression, in response to EGF stimulation. The EGFR/erbB-2 chimera was significantly more active in inducing DNA synthesis than the EGFR when either was expressed in NIH 3T3 cells. Analysis of biochemical pathways implicated in signal transduction by growth factor receptors indicated that both phospholipase C type γ (PLC-γ) and the p21ras GTPase-activating protein (GAP) are substrates for the erbB-2 kinase in NIH 3T3 fibroblasts. However, under conditions in which activation of the erbB-2 kinase induced DNA synthesis at least fivefold more efficiently than the EGFR, the levels of erbB-2- or EGFR-induced tyrosine phosphorylation of PLC-γ and GAP were comparable. In addition, the stoichiometry of tyrosine phosphorylation of these putative substrates by erbB-2 appeared to be at least an order of magnitude lower than that induced by platelet-derived growth factor receptors at comparable levels of mitogenic potency. Thus, our results indicate that differences in tyrosine phosphorylation of PLC-γ and GAP do not account for the differences in mitogenic activity of the erbB-2 kinase compared with either the EGFR or platelet-derived growth factor receptor in NIH 3T3 fibroblasts.",
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