Ras activates Raf, leading to the extracellular-regulated kinase (ERK)–mitogen-activated protein kinase pathway, which is involved in a variety of cellular, physiological, and pathological responses. Thus, regulators of this Ras–Raf interaction play crucial roles in these responses. In this study, we report a novel regulator of the Ras–Raf interaction named DA-Raf1. DA-Raf1 is a splicing isoform of A-Raf with a wider tissue distribution than A-Raf. It contains the Ras-binding domain but lacks the kinase domain, which is responsible for activation of the ERK pathway. As inferred from its structure, DA-Raf1 bound to activated Ras as well as M-Ras and interfered with the ERK pathway. The Ras–ERK pathway is essential for the negative regulation of myogenic differentiation induced by growth factors. DA-Raf1 served as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation. These results imply that DA-Raf1 is the first identified competent, intrinsic, dominant-negative antagonist of the Ras–ERK pathway.
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4 June 2007
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May 29 2007
DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras–ERK pathway, is required for myogenic differentiation
Takashi Yokoyama,
Takashi Yokoyama
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Kazunori Takano,
Kazunori Takano
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Akira Yoshida,
Akira Yoshida
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
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Fumiko Katada,
Fumiko Katada
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
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Peng Sun,
Peng Sun
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Tadaomi Takenawa,
Tadaomi Takenawa
2Department of Biochemistry, Institute of Medical Science, University of Tokyo, Minatoku, Tokyo 108-8639, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Toshiwo Andoh,
Toshiwo Andoh
4Department of Genetic Engineering, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
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Takeshi Endo
Takeshi Endo
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Takashi Yokoyama
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Kazunori Takano
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Akira Yoshida
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
Fumiko Katada
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
Peng Sun
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Tadaomi Takenawa
2Department of Biochemistry, Institute of Medical Science, University of Tokyo, Minatoku, Tokyo 108-8639, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Toshiwo Andoh
4Department of Genetic Engineering, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
Takeshi Endo
1Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Correspondence to Takeshi Endo: [email protected]
Abbreviations used in this paper: CRD, cysteine-rich domain; ERK, extracellular-regulated kinase; MEK, MAPK and ERK kinase; MyHC, myosin heavy chain; PI3K, phosphatidylinositol 3-kinase; RBD, Ras-binding domain; RIPA, radioimmunoprecipitation assay; Spry, Sprouty; TnT, troponin T.
Received:
March 29 2007
Accepted:
May 02 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 177 (5): 781–793.
Article history
Received:
March 29 2007
Accepted:
May 02 2007
Citation
Takashi Yokoyama, Kazunori Takano, Akira Yoshida, Fumiko Katada, Peng Sun, Tadaomi Takenawa, Toshiwo Andoh, Takeshi Endo; DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras–ERK pathway, is required for myogenic differentiation . J Cell Biol 4 June 2007; 177 (5): 781–793. doi: https://doi.org/10.1083/jcb.200703195
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