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  • Original Paper
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Transformation potency of ErbB heterodimer signaling is determined by B-Raf kinase

Oncogene volumeĀ 23,Ā pages 5023ā€“5031 (2004)Cite this article

Abstract

Cellular transformation occurs only in cells that express both ErbB1 and ErbB4 receptors, but not in cells expressing only one or the other of these receptors. However, when both receptors are coexpressed and ligand-stimulated, they interact with virtually the same adaptor/effector proteins as when expressed singly. To reveal the underlying regulatory mechanism of the kinase/phosphatase network in ErbB homo- and heterodimer receptor signaling, extracellular signal-regulated kinase (ERK) and Akt activities were evaluated in the presence of several enzyme inhibitors in ligand-induced cells expressing ErbB1 (E1), ErbB4 (E4), and ErbB1/ErbB4 (E1/4) receptor. The PP2A inhibitor okadaic acid showed receptor-specific inhibitory profiles for ERK and Akt activities. Moreover, B-Raf isolated only from E1/4 cells could induce in vitro phosphorylation for MEK; this B-Raf kinase activity was abolished by pretreatment of the cells with okadaic acid. Our study further showed that the E1/4 cell-specific B-Raf activity was stimulated by PLCĪ³ and subsequent Rap1 activation. The present study suggests that B-Raf kinase, which was specifically activated in the cells coexpressing ErbB1 and ErbB4 receptors, elevates total ERK activity within the cell and, therefore, can induce cellular transformation.

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Abbreviations

CHO:

Chinese hamster ovary

EGFR:

EGF receptor

EGF:

epidermal growth factor

HRG:

heregulin

MAPK:

mitogen-activated protein kinase

MEK:

extracellular signal-regulated kinase kinase

ERK:

extracellular signal-regulated kinase

SH2:

Src homology 2 domain

Grb2:

growth factor receptor-binding protein 2

Shc:

Src homology and collagen domain protein

PI3K:

phosphatidylinositol 3ā€²-kinase

PLCĪ³:

phosphoinositide-specific phospholipase C-Ī³

PKA:

protein kinase A

PH domain:

pleckstrin homology domain

PP2A:

protein phosphatase 2A

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Acknowledgements

We thank Ms Mihoro Saeki for constructing CHO cells expressing ErbB1 and ErbB4 receptors. We also thank Dr Takashi Naka for critically reading the manuscript and Mr Akinobu Fukuzaki for preparing the manuscript.

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Authors and Affiliations

  1. Bioinformatics Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    M Hatakeyama,Ā N Yumoto,Ā X YuĀ &Ā A Konagaya

  2. Protein Research Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    M ShirouzuĀ &Ā S Yokoyama

  3. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    S Yokoyama

  4. Cellular Signaling Laboratory and Structurome Group, RIKEN Harima Institute at SPring-8, 1-1-1 Kohto, Mikazuki-cho, Sayo, 679-5148, Hyogo, Japan

    S Yokoyama

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  1. M Hatakeyama
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Correspondence to M Hatakeyama.

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Hatakeyama, M., Yumoto, N., Yu, X. et al. Transformation potency of ErbB heterodimer signaling is determined by B-Raf kinase. Oncogene 23, 5023ā€“5031 (2004). https://doi.org/10.1038/sj.onc.1207664

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