Abstract
The Raf-MEK-ERK protein kinase cascade is a highly conserved signaling pathway that is pivotal in relaying environmental cues from the cell surface to the nucleus. Three Raf isoforms, which share great sequence and structure similarities, have been identified in mammalian cells. We have previously identified Raf kinase inhibitor protein (RKIP) as a negative regulator of the Raf-MEK-ERK signaling pathway by specifically binding to the Raf-1 isoform. We show here that RKIP also antagonizes kinase activity of the B-Raf isoform. Yeast two-hybrid and coimmunoprecipitation experiments indicated that RKIP specifically interacted with B-Raf. Ectopic expression of RKIP antagonized the kinase activity of B-Raf. We showed that the effects of RKIP on B-Raf functions were independent of its known inhibitory action on Raf-1. The expression levels of RKIP in melanoma cancer cell lines are low relative to primary melanocytes. Forced expression of RKIP partially reverted the oncogenic B-Raf kinase-transformed melanoma cancer cell line SK-Mel-28. The low expression of RKIP and its antagonistic action on B-Raf suggests that RKIP may play an important role in melanoma turmorgenesis.
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Acknowledgements
We thank K-L Guan and William Maltese for plasmid constructs, M Baccarini for the Raf-1−/− MEF cells. We also thank John Sedivy for his continued support and Walter Kolch for sharing results on RKIP expression in melanoma before publication. This work was supported by NIH grants to KCY (R01 GM64767).
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Park, S., Yeung, M., Beach, S. et al. RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24, 3535–3540 (2005). https://doi.org/10.1038/sj.onc.1208435
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DOI: https://doi.org/10.1038/sj.onc.1208435
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