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Published online May 29, 2007
doi:10.1083/jcb.200703195
The Journal of Cell Biology, Vol. 177, No. 5, 781-793
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Yokoyama et al.
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Article

 DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras–ERK pathway, is required for myogenic differentiation

Takashi Yokoyama1,3, Kazunori Takano1,3, Akira Yoshida1, Fumiko Katada1, Peng Sun1,3, Tadaomi Takenawa2,3, Toshiwo Andoh4, and Takeshi Endo1,3

1 Department of Biology, Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan
2 Department of Biochemistry, Institute of Medical Science, University of Tokyo, Minatoku, Tokyo 108-8639, Japan
3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
4 Department of Genetic Engineering, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan

Correspondence to Takeshi Endo: t.endo{at}faculty.chiba-u.jp

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.

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.


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