Differential signaling by an anti-p185(HER2) antibody and heregulin

Xiao Feng Le, Ratna Vadlamudi, Amanda McWatters, Duk Soo Bae, Gordon B. Mills, Rakesh Kumar, Robert C. Bast

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

To understand the molecular mechanisms by which anti-p185(HER2) antibody and the ligand heregulin inhibit tumor growth, we have investigated several signaling proteins and pathways. We report here that anti-p185(HER2) monoclonal antibody ID5 induced tyrosine phosphorylation of HER2 in SKBr3 breast cancer cells that overexpress p185(HER2). Heregulin β1 induced phosphorylation of both HER3 and HER2. ID5 produced a greater association of phospholipase C (PLC)-γ1 with HER2 than did heregulin. Concordantly, ID5, but not heregulin, increased PLC-γ1 activity. However, the G1 cell cycle arrest and induction of p27(Kip1) produced by ID5 were not affected by the inhibition of PLC-γ. ID5 preferentially induced binding of the M(r) 46,000 isoform of SHC to HER2, whereas heregulin preferentially induced binding of the M(r) 52,00 isoform of SHC to HER3. Heregulin, but not ID5, induced the p85 subunit of phosphatidylinositol 3'-kinase (PI3-K) to interact with HER3. Heregulin induced sustained activation of PI3-K signaling, whereas ID5 had only a transient effect. Heregulin, but not ID5, activated the c-Jun-NH2- terminal kinase cascade. Pretreatment of SKBr3 cells with ID5 decreased heregulin-induced association of HER2 with HER3 as well as the activation of c-Jun-NH2-terminal kinase and PI3-K activities. Inhibition of the mitogen- activated protein kinase pathway in SKBr3 cells did not affect heregulin- induced G2-M-phase arrest, apoptosis, and differentiation. Heregulin-induced apoptosis could be blocked by inhibition of p70s6k, but not by inhibition of PI3-K. Heregulin-induced differentiation could be eliminated by inhibition of PI3-K. We conclude that ID5 and heregulin signal via different pathways, although both agents can inhibit the clonogenic growth of cells that overexpress HER2.

Original languageEnglish (US)
Pages (from-to)3522-3531
Number of pages10
JournalCancer Research
Volume60
Issue number13
StatePublished - Jul 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Le, X. F., Vadlamudi, R., McWatters, A., Bae, D. S., Mills, G. B., Kumar, R., & Bast, R. C. (2000). Differential signaling by an anti-p185(HER2) antibody and heregulin. Cancer Research, 60(13), 3522-3531.