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

M Hatakeyama1, N Yumoto, X Yu

  • 1Bioinformatics Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. marikoh@gsc.riken.jp

Oncogene
|April 6, 2004
PubMed

Insights

Cellular transformation requires coexpression of ErbB1 and ErbB4 receptors. This study identifies B-Raf kinase as a key mediator, activated by ErbB1/ErbB4 coexpression, leading to ERK activation and transformation.

Area of Science:

  • Cellular and Molecular Biology
  • Signal Transduction
  • Oncology

Background:

  • Cellular transformation is linked to ErbB receptor signaling.
  • ErbB1 and ErbB4 receptor coexpression is necessary for transformation, but the underlying mechanism is unclear.
  • Receptor coexpression does not alter interactions with common adaptor proteins.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the kinase/phosphatase network in ErbB receptor signaling.
  • To investigate the role of specific kinases and phosphatases in ErbB1/ErbB4-mediated cellular transformation.
  • To identify key signaling molecules responsible for ErbB1/ErbB4 heterodimer-induced transformation.

Main Methods:

  • Ligand-induced signaling in cells expressing ErbB1, ErbB4, or both.
  • Evaluation of extracellular signal-regulated kinase (ERK) and Akt activities using enzyme inhibitors.
  • In vitro kinase assays with isolated B-Raf and MEK.
  • Assessment of PLC gamma and Rap1 activation.

Main Results:

  • PP2A inhibition by okadaic acid revealed receptor-specific effects on ERK and Akt.
  • B-Raf kinase, isolated exclusively from ErbB1/ErbB4 coexpressing cells, phosphorylated MEK.
  • Okadaic acid pretreatment abolished B-Raf kinase activity in ErbB1/ErbB4 cells.
  • ErbB1/ErbB4 cell-specific B-Raf activity was stimulated by PLC gamma and Rap1 activation.

Conclusions:

  • B-Raf kinase is specifically activated in cells coexpressing ErbB1 and ErbB4 receptors.
  • Activated B-Raf kinase elevates total ERK activity, promoting cellular transformation.
  • This study reveals a novel signaling pathway involving B-Raf in ErbB1/ErbB4-driven transformation.

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