Regulation of raf-1 by direct feedback phosphorylation
Regulation of raf-1 by direct feedback phosphorylation
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DOI：
10.1016/j.molcel.2004.11.055
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发表时间：
2005-01-21
期刊：
影响因子：
16
通讯作者：
Morrison, DK
中科院分区：
文献类型：
--
作者：
Dougherty, MK;Müller, J;Morrison, DK
Raf-1激酶是一种重要的信号分子，在Ras通路中发挥作用，将促有丝分裂、分化和致癌信号传递给下游激酶MEK和ERK。由于Raf-1在细胞信号传导中的重要作用，必须精确控制Raf-1的活性。以前的研究表明，磷酸化是Raf-1激活所必需的，在这里，我们确定了六个磷酸化位点，有助于有丝分裂原刺激后下调Raf-1。其中5个位点是激活ERK的脯氨酸导向靶点，所有6个位点的磷酸化都需要MEK信号传导，表明存在负反馈机制。这六个位点的过度磷酸化抑制Ras/Raf-1相互作用，并使Raf-1对额外的刺激脱敏。过度磷酸化/脱敏的Raf-1随后被去磷酸化，并通过与蛋白磷酸酶PP 2A和脯氨酰异构酶Pin 1的相互作用返回到信号活性状态。这些发现阐明了一个关键的Raf-1的调节机制，有助于敏感，时间调节Ras信号。
The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.