Peptides containing a consensus Ras binding sequence from Raf-1 and the GTPase activating protein NF1 inhibit Ras function
Peptides containing a consensus Ras binding sequence from Raf-1 and the GTPase activating protein NF1 inhibit Ras function
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DOI：
10.1073/pnas.93.4.1577
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发表时间：
1996-02-20
影响因子：
11.1
通讯作者：
Campbell, S
中科院分区：
文献类型：
--
作者：
Clark, GJ;Drugan, JK;Campbell, S
Ras介导的信号转导和转化中的一个关键事件涉及Ras与其下游效应靶的相互作用。尽管大量证据已经确定Raf-I丝氨酸/苏氨酸激酶是Ras功能的关键效应子，但越来越多的证据表明Ras功能是通过与多种效应子相互作用来介导的，以触发Raf-independent信号传导途径。除了两种Ras GTP酶激活蛋白（GAP; p120-和NF 1-GAP）外，其他候选效应物包括Ras相关Ral蛋白（RalGDS和RGL）和磷脂酰肌醇3-激酶的激活剂。Ras与其效应子之间的相互作用需要完整的Ras效应子结构域，并涉及活性Ras-GTP的优先识别。令人惊讶的是，这些功能多样的效应物缺乏显著的序列同源性，并且没有描述共有Ras结合序列。我们现在已经鉴定了Ras效应子的子集之间共享的共有Ras结合序列。我们还表明，含有来自Raf-I（RKTFLKCA）和NF 1-GAP（RRFFLDIA）的该序列的肽阻断NF 1-GAP对Ras GT3活性的刺激和Pas介导的促分裂原活化蛋白激酶的活化。总之，一致的Ras-GTP结合序列的鉴定为不同效应蛋白与Ras-GTP相互作用的能力建立了结构基础。此外，我们证明，含有Ras-GTP结合序列的肽可以阻断Ras功能，这为开发抗Pas药物迈出了一步。
A key event in Ras-mediated signal transduction and transformation involves Ras interaction with its downstream effector targets. Although substantial evidence has established that the Raf-l serine/threonine kinase is a critical effector of Ras function, there is increasing evidence that Ras function is mediated through interaction with multiple effecters to trigger Raf-independent signaling pathways. In addition to the two Ras GTPase activating proteins (GAPs; p120- and NF1-GAP), other candidate effecters include activators of the Ras-related Ral proteins (RalGDS and RGL) and phosphatidylinositol 3-kinase. Interaction between Ras and its effecters requires an intact Ras effector domain and involves preferential recognition of active Ras-GTP. Surprisingly, these functionally diverse effecters lack significant sequence homology and no consensus Ras binding sequence has been described. We have now identified a consensus Ras binding sequence shared among a subset of Ras effecters. We have also shown that peptides containing this sequence from Raf-l (RKTFLKCA) and NF1-GAP (RRFFLDIA) block NF1-GAP stimulation of Ras GTPase activity and Pas-mediated activation of mitogen-activated protein kinases. In summary, the identification of a consensus Ras-GTP binding sequence establishes a structural basis for the ability of diverse effector proteins to interact with Ras-GTP. Furthermore, our demonstration that peptides that contain Ras-GTP binding sequences can block Ras function provides a step toward the development of anti-Pas agents.