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DA-Raf1是Ras-ERK信号通路中一种有效的内源性显性负性拮抗剂，是肌源性分化所必需的。

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

作者信息

Yokoyama Takashi, Takano Kazunori, Yoshida Akira, Katada Fumiko, Sun Peng, Takenawa Tadaomi, Andoh Toshiwo, Endo Takeshi

机构信息

Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.

出版信息

J Cell Biol. 2007 Jun 4;177(5):781-93. doi: 10.1083/jcb.200703195. Epub 2007 May 29.

DOI:10.1083/jcb.200703195
PMID:17535970
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2064279/
Abstract

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.

摘要

Ras激活Raf，从而导致细胞外调节激酶（ERK）-丝裂原活化蛋白激酶信号通路的激活，该信号通路参与多种细胞、生理和病理反应。因此，Ras-Raf相互作用的调节因子在这些反应中起着关键作用。在本研究中，我们报道了一种名为DA-Raf1的Ras-Raf相互作用的新型调节因子。DA-Raf1是A-Raf的一种剪接异构体，其组织分布比A-Raf更广泛。它含有Ras结合结构域，但缺乏负责激活ERK信号通路的激酶结构域。从其结构推断，DA-Raf1与活化的Ras以及M-Ras结合，并干扰ERK信号通路。Ras-ERK信号通路对于生长因子诱导的成肌分化的负调控至关重要。DA-Raf1通过诱导细胞周期停滞、肌细胞生成素和其他肌肉特异性蛋白的表达以及肌管形成，作为成肌分化的正调节因子。这些结果表明，DA-Raf1是首个被鉴定出的Ras-ERK信号通路的有效、内在、显性负性拮抗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/bbe2e3c72940/jcb1770781f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/94e4a4546e0c/jcb1770781f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/846d31242f51/jcb1770781f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/7628481da2be/jcb1770781f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/2536d1644ff7/jcb1770781f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/33312bd59e2e/jcb1770781f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/8d084af12181/jcb1770781f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/d7e78a01ab69/jcb1770781f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/bbe2e3c72940/jcb1770781f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/94e4a4546e0c/jcb1770781f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/846d31242f51/jcb1770781f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/7628481da2be/jcb1770781f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/2536d1644ff7/jcb1770781f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/33312bd59e2e/jcb1770781f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/8d084af12181/jcb1770781f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/d7e78a01ab69/jcb1770781f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ec/2064279/bbe2e3c72940/jcb1770781f08.jpg

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