Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes
Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes
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DOI：
10.1128/mcb.01882-06
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发表时间：
2007-04-01
影响因子：
5.3
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
--
作者：
Roose, Jeroen P.;Mollenauer, Marianne;Weiss, Arthur
Ras的激活对淋巴细胞的发育和效应功能至关重要。T和B淋巴细胞都含有两种类型的Ras激活剂：普遍表达的SOS和特异性表达的Ras鸟苷酸释放蛋白（RasGRP）。需要两种激活剂是神秘的，因为两者都在抗原受体刺激后被激活。此外，RasGRP 1似乎以一种未知的方式对SOS起主导作用。SOS的晶体结构提供了一个线索：一个不寻常的变构Ras-GTP结合口袋。在这里，我们证明了RasGRP以两种方式协调Ras信号传导：（i）通过直接激活Ras和（ii）通过促进SOS与RasGTP结合变构口袋的启动。预充增强了SOS的体内活性，并创建了一个正RasGTP-SOS反馈循环，其作用相当于Ras活性的变阻器。如果没有RasGRP 1，这个循环的启动会受到损害，因为SOS的催化剂是它自己的产物（RasGTP）-因此RasGRP 1占主导地位。在T-和B-细胞系中引入活性Ras样分子（RasV 12 C40）可以替代RasGRP功能并通过其变构口袋增强SOS的活性。不寻常的RasGRP-SOS相互作用导致敏感和强大的Ras激活，这是单独使用任何一种激活剂都无法实现的。我们假设，这种机制使淋巴细胞能够最大限度地响应生理低水平的刺激。
Ras activation is crucial for lymphocyte development and effector function. Both T and B lymphocytes contain two types of Ras activators: ubiquitously expressed SOS and specifically expressed Ras guanyl nucleotide-releasing protein (RasGRP). The need for two activators is enigmatic since both are activated following antigen receptor stimulation. In addition, RasGRP1 appears to be dominant over SOS in an unknown manner. The crystal structure of SOS provides a clue: an unusual allosteric Ras-GTP binding pocket. Here, we demonstrate that RasGRP orchestrates Ras signaling in two ways: (i) by activating Ras directly and (ii) by facilitating priming of SOS with RasGTP that binds the allosteric pocket. Priming enhances SOS' in vivo activity and creates a positive RasGTP-SOS feedback loop that functions as a rheostat for Ras activity. Without RasGRP1, initiation of this loop is impaired because SOS' catalyst is its own product (RasGTP)-hence the dominance of RasGRP1. Introduction of an active Ras-like molecule (RasV12C40) in T- and B-cell lines can substitute for RasGRP function and enhance SOS' activity via its allosteric pocket. The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. We hypothesize that this mechanism enables lymphocytes to maximally respond to physiologically low levels of stimulation.