Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells

Laura Sepp-Lorenzino, Inge Eberhard, Zhenping Ma, Cheryl Cho, Hubert Serve, Franklin Liu, Neal Rosen, Ruth Lupu

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185(c-erbB-2), recent evidence suggests that other receptors of the erbB family, including p180(erbB-3) and p180(erbB-4), are their true cognate receptors. Stimulation of MDA MB-453 cells with HRGβ2 resulted in the tyrosine phosphorylation of p185(c-erbB-2), and p180(erbB-4) in a time-and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185(c-erbB-2) and p180(erbB-4). In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185(c-erbB-2), p180(erbB-4) and SHC. Activation of mitogen-activated protein kinase (MAPR) (> 30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos (> 200-fold). These observations suggest that p21(ras) activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185(c-erbB-2) and p180(erbB-4), revealed a preferential association with activated p180(erbB-4). These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained.

Original languageEnglish (US)
Pages (from-to)1679-1687
Number of pages9
Issue number8
StatePublished - 1996


  • Heregulin
  • Signaling
  • erbB receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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