CD147 inhibits the nuclear factor of activated T-cells by impairing vav1 and rac1 downstream signaling
CD147 inhibits the nuclear factor of activated T-cells by impairing vav1 and rac1 downstream signaling
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DOI：
10.1074/jbc.m708566200
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发表时间：
2008-02-29
影响因子：
4.8
通讯作者：
Bustelo, Xose R.
中科院分区：
文献类型：
--
作者：
Ruiz, Sergio;Castro-Castro, Antonio;Bustelo, Xose R.
CD147是一种跨膜蛋白，在生殖、视觉和神经系统的发育和功能中发挥着至关重要的作用。CD147在T细胞中也发挥正负作用，其作用机制尚不清楚。在本研究中，我们分析了CD147在T细胞受体信号反应中的表达、定位和功能。我们发现CD147是T细胞免疫突触的一个组成部分，它的过度表达导致了由rac1交换因子Vav1诱导的NF-AT(活化T细胞核因子)活性的抑制。这种抑制活性是由CD147胞内尾巴介导的，完全不依赖于它的胞外或跨膜区域。CD147对Vav1通路影响的分子解剖表明，其抑制作用发生在Vav1和rac1的下游，而丝氨酸/苏氨酸激酶JNK和Ak1的上游。CD147对这些通路的干扰具有高度的特异性，因为CD147的过度表达不会影响其他GDP/GTP交换因子的活性或ERK级联反应的刺激。最后，我们发现，Jurkat细胞中的CD147基因敲除促进了更高水平的核因子-AT刺激和T细胞受体交叉连接上的Ak1磷酸化。相反，CD147的缺失不会影响参与相同细胞反应的其他信号级联反应。综上所述，这些结果表明，CD147通过选择性地抑制Vav1/rac1途径的特定下游元件，参与了T细胞反应的负调控。
CD147 is a transmembrane protein that plays crucial roles in the development and function of the reproductive, visual, and nervous systems. CD147 also exerts positive and negative actions in T-cells by still obscure mechanisms. In this study, we have analyzed the expression, localization, and function of CD147 during T-cell receptor signaling responses. We show here that CD147 is an integral component of the T-cell immune synapse and that its overexpression leads to the inhibition of NF-AT ( nuclear factor of activated T-cells) activity induced by Vav1, a Rac1 exchange factor. This inhibitory activity is mediated by the CD147 intracellular tail and is totally independent of its extracellular or transmembrane regions. The molecular dissection of the influence of CD147 on the Vav1 pathway indicates that its inhibitory action takes place downstream of Vav1 and Rac1 but upstream of the serine/threonine kinases JNK and Pak1. The interference of CD147 with these pathways is highly specific because the overexpression of CD147 does not affect the activity of other GDP/GTP exchange factors or the stimulation of the ERK cascade. Finally, we show that the CD147 knockdown in Jurkat cells promotes higher levels of NF-AT stimulation and Pak1 phosphorylation upon T-cell receptor cross-linking. Instead, the lack of CD147 does not affect other signaling cascades that participate in the same cellular response. Taken together, these results indicate that CD147, via the selective inhibition of specific downstream elements of the Vav1/Rac1 route, contributes to the negative regulation of T-cell responses.