Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen
Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen
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DOI：
10.1128/mcb.24.14.6311-6323.2004
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发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Schrader, JW
中科院分区：
文献类型：
--
作者：
Ehrhardt, A;David, MD;Schrader, JW
虽然Ras家族的GTP酶参与了细胞调控的许多方面，但对单个家族成员的作用知之甚少。在此，我们分析了H-Ras、N-Ras、K-Ras 4 B和M-Ras通过两种类型的外部刺激、生长因子和B或T淋巴细胞（BCR和TCR）的抗原受体的连接而活化的机制。生长因子白细胞介素-3、集落刺激因子1和表皮生长因子都优先激活M-Ras和K-Ras 4 B，而不是H-Ras或N-Ras。M-Ras和K-Ras 4 B的优先激活依赖于它们的多碱基羧基末端的存在，这将它们引导到高浮力密度的膜结构域中，其中也存在激活的受体、适配器和mSos。相比之下，BCR或TCR的连接会导致H-Ras、N-Ras和K-Ras 4 B的激活，但不会导致M-Ras的激活。这种激活模式不受Ras蛋白定位于膜结构域的影响。H-Ras、N-Ras和K-Ras 4 B的激活反而依赖于磷脂酶C-γ和RasGRP的存在。因此，导致Ras蛋白激活的分子机制随刺激而变化，并且可以受到与激活的受体共定位或对由刺激激活的交换因子的差异敏感性的影响。
Although GTPases of the Ras family have been implicated in many aspects of the regulation of cells, little is known about the roles of individual family members. Here, we analyzed the mechanisms of activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by two types of external stimuli, growth factors and ligation of the antigen receptors of B or T lymphocytes (BCRs and TCRs). The growth factors interleukin-3, colony-stimulating factor 1, and epidermal growth factor all preferentially activated M-Ras and K-Ras 4B over H-Ras or N-Ras. Preferential activation of M-Ras and K-Ras 4B depended on the presence of their polybasic carboxy termini, which directed them into high-buoyant-density membrane domains where the activated receptors, adapters, and mSos were also present. In contrast, ligation of the BCR or TCR resulted in activation of H-Ras, N-Ras, and K-Ras 4B, but not M-Ras. This pattern of activation was not influenced by localization of the Ras proteins to membrane domains. Activation of H-Ras, N-Ras, and K-Ras 4B instead depended on the presence of phospholipase C-gamma and RasGRP. Thus, the molecular mechanisms leading to activation of Ras proteins vary with the stimulus and can be influenced by either colocalization with activated receptors or differential sensitivity to the exchange factors activated by a stimulus.