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

Bioinformatics Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Oncogene (Impact Factor: 8.46). 07/2004; 23(29):5023-31. DOI: 10.1038/sj.onc.1207664
Source: PubMed


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 PLC gamma 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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Available from: Akihiko Konagaya, Apr 08, 2014
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    • "As an additional measure of cAMP signaling in CNS and PNS neurons, we used phospho- PKA (p-PKA) substrate antibodies as an indirect read-out of cAMP-mediated PKA activation (Hatakeyama et al., 2004; Lei et al., 2007; Schmitt and Stork, 2002). In total cell lysates from CNS and PNS neurons, we detected four prominent bands consistently (100, 70, 40, and 32 kDa, respectively) on Western blot (Fig. 1d). "
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    • "If this is the case, Rap1 activity would be less influential on ERK activity. In order to confirm the lesser impact of Rap1 activity on ERK activity, we compared ERK activity 5 min after 10 nM EGF treatment in the presence or absence of the PLCγ inhibitor U73122, which can indirectly suppress Rap1 activity in CHO cells (Tables 1, no. 7) [21]. U73122 showed less effect on ERK activity both in E1 and E1/4 cells, and is consistent with the above-mentioned perspective based on steady-state analysis. "
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