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  • Original Paper
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Molecular requirements for the effect of neuregulin on cell spreading, motility and colony organization

Abstract

Neuregulin can trigger morphogenetic signals in cells both in vivo and in culture through the activation of receptors from the ErbB family. We have ectopically expressed various ErbB-receptors in 32D myeloid cells lacking endogenous ErbB-proteins, and in CHO cells, which express only ErbB-2. We show here that activation of ErbB-3/ErbB-2 heterodimeric receptors triggers PI3-kinase-dependent lamellipodia formation and spreading, while individual ErbB-receptor homodimers as well as ErbB-3/ErbB-1 heterodimers are much less effective. CHO cells expressing ErB-3/ErbB-2 together with N-cadherin, an adhesion receptor, form epithelioid colonies. Neuregulin activates cell motility leading to transition of these colonies into ring-shaped multicellular arrays, similar to those induced by neuregulin in epithelial cells of different types (Chausovsky et al., 1998). This process requires both PI3-kinase and MAP kinase kinase activity and depends on coordinated changes in the actin- and microtubule-based cytoskeleton. Transactivation of ErbB-2 is not sufficient for the activation of cell motility and ring formation, and the C-terminal domain of ErbB-3 bearing the docking sites for the p85 subunit of PI3-kinase is essential for these morphogenetic effects. Thus, ErbB-3 in conjunction with ErbB-2 mediates, via its C-terminal domain, cytoskeletal and adhesion alterations which activate cell spreading and motility, leading to the formation of complex structures such as multicellular rings.

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Acknowledgements

This study was supported by grants from the Minerva Foundation (Munich, Germany) and the Israel Science Foundation (to AD Bershadsky and B Geiger), and from The Israel Ministry of Science (to AD Bershadsky) and La Fondation Raphael et Regina Levy (to AD Bershadsky and M Elbaum). Participation of M Elbaum was supported in part by the Gerhard MJ Schmidt Minerva Center for Supramolecular Architecture, and by the Israel Science Foundation. B Geiger holds the E Neter Chair in Cell and Tumor Biology. B Geiger and AD Bershadksy acknowledge support of Yad Abraham Center for Cancer Diagnostics and Therpay. We are grateful to Orna Yeger for the assistance in the scanning electron microscopy.

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Chausovsky, A., Waterman, H., Elbaum, M. et al. Molecular requirements for the effect of neuregulin on cell spreading, motility and colony organization. Oncogene 19, 878–888 (2000). https://doi.org/10.1038/sj.onc.1203410

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