Jirakulaporn Tanawat, Muslin Anthony J
Center for Cardiovascular Research, the Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
J Biol Chem. 2004 Jun 25;279(26):27807-15. doi: 10.1074/jbc.M401210200. Epub 2004 Apr 19.
The Ras-extracellular signal-regulated kinase (ERK) cascade is a critical intracellular signaling pathway that regulates growth, survival, and differentiation. Previous work established that Ras-GTP binds to, and facilitates the activation of, the protein kinase Raf-1. Recently, it was demonstrated that the cation diffusion facilitator (CDF) proteins are involved in Ras-ERK signaling by use of a Caenorhabditis elegans genetic screen that identified suppressors of activated Ras. In the current work, we demonstrate that CDF proteins may function downstream of Ras, but upstream of Raf-1 in Xenopus oocytes. We also show that the C. elegans protein CDF-1 and its mammalian homologue ZnT-1 bind to the amino-terminal regulatory portion of Raf-1 and promote the biological and enzymatic activity of Raf-1. Furthermore, we show that Zn(2+) inhibits Raf-1 binding to ZnT-1. We propose a model in which CDF protein binding facilitates Raf-1 activation.
Ras-细胞外信号调节激酶（ERK）级联反应是一条关键的细胞内信号通路，可调节细胞生长、存活和分化。先前的研究表明，Ras-GTP结合并促进蛋白激酶Raf-1的激活。最近，通过利用秀丽隐杆线虫遗传筛选鉴定出活化Ras的抑制因子，证明阳离子扩散促进因子（CDF）蛋白参与Ras-ERK信号传导。在当前的研究中，我们证明在非洲爪蟾卵母细胞中，CDF蛋白可能在Ras下游发挥作用，但在Raf-1上游。我们还表明，秀丽隐杆线虫蛋白CDF-1及其哺乳动物同源物ZnT-1与Raf-1的氨基末端调节部分结合，并促进Raf-1的生物学和酶活性。此外，我们表明Zn(2+)抑制Raf-1与ZnT-1的结合。我们提出了一个模型，其中CDF蛋白结合促进Raf-1激活。
