Direct stimulation of ERBB2 highlights a novel cytostatic signaling pathway driven by the receptor Thr701 phosphorylation: Scientific Reports

M. Gaviraghi, A. Rabellino, A. Andolfo, Matthias Brand, C. Brombin, P. Bagnato, G. De Feudis, A. Raimondi, A. Locatelli, D. Tosoni, D. Mazza, L. Gianni, G. Tonon, Y. Yarden, C. Tacchetti, T. Daniele

Research output: Contribution to journalArticlepeer-review

Abstract

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor. In this paper, we found that antibodies (Abs) targeting different epitopes on the ERBB2 extracellular domain foster the activation of ERBB2 homodimers, and surprisingly induce a unique cytostatic signaling cascade promoting an ERK-dependent ERBB2 Thr701 phosphorylation, leading to AKT de-phosphorylation, via PP2A Ser/Thr phosphatases. Furthermore, the immunophilin Cyclophilin A plays a crucial role in this pathway, acting as a negative modulator of AKT de-phosphorylation, possibly by competing with Ser/Thr phosphatases for binding to AKT. Altogether, our data show that Ab recognizing ERBB2 extracellular domain function as receptor agonists, promoting ERBB2 homodimer activation, leading to an anti-proliferative signaling. Thus, the ultimate outcome of ERBB2 activity might depend on the dimerization status: pro-oncogenic in the hetero-, and anti-oncogenic in the homo-dimeric form. © 2020, The Author(s).
Original languageEnglish
Article number16906
JournalSci. Rep.
Volume10
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • cytostatic agent
  • epidermal growth factor receptor 2
  • ERBB2 protein, human
  • mitogen activated protein kinase
  • protein kinase B
  • protein tyrosine kinase
  • cell proliferation
  • cell transformation
  • dimerization
  • human
  • immunology
  • metabolism
  • phosphorylation
  • physiology
  • signal transduction
  • tumor cell line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cytostatic Agents
  • Dimerization
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Signal Transduction

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