Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules.
Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules.
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DOI：
10.3389/fimmu.2013.00139
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发表时间：
2013
影响因子：
7.3
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
So T;Croft M
磷酸肌醇3-激酶（PI 3 K）和Akt（蛋白激酶B）的激活是由许多细胞类型上的一系列膜结合受体触发的常见应答。在T淋巴细胞中，PI 3 K-Akt通路促进效应细胞的克隆扩增、分化和存活，并抑制调节性T细胞的产生。PI 3 K活化由通过T细胞受体（TCR）和共刺激受体CD 28的信号严格控制，然而，来自额外共受体的持续和周期性信号现在被认为是该途径活化的关键贡献者。越来越多的证据表明，肿瘤坏死因子受体（TNFR）超家族的许多成员TNFR 2（TNFRSF 1B）、0X 40（TNFRSF 4）、4-1BB（TNFRSF 9）、HVEM（TNFRSF 14）和DR 3（TNFRSF 25）在T细胞上是组成型的或可诱导的，可以直接或间接地促进PI 3 K-Akt途径中的活性。我们讨论了最近的数据表明，一个TNFR家族分子的连接组织的信号体，通过TNFR相关因子（TRAF）衔接蛋白在T细胞膜脂质微区，导致随后的积累高度集中的仓库PI 3 K和Akt在接近TCR信号单位。我们认为这可能是一种可推广的机制，适用于其他TNFR家族分子，这将导致这些信号体对增强和维持TCR触发的PI 3 K和Akt活化的定量贡献。我们还回顾了其他TNFR分子，如CD 40（TNFRSF 5），RANK（TNFRSF 11 A），FN 14（TNFRSF 12 A），TACI（TNFRSF 13 B），BAFFR（TNFRSF 13 C）和NGFR（TNFRSF 16），通过招募PI 3 K或Akt进入其信号复合物的类似能力，在不同细胞类型中激活该途径的数据。
Activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a common response triggered by a range of membrane-bound receptors on many cell types. In T lymphocytes, the PI3K-Akt pathway promotes clonal expansion, differentiation, and survival of effector cells and suppresses the generation of regulatory T cells. PI3K activation is tightly controlled by signals through the T cell receptor (TCR) and the co-stimulatory receptor CD28, however sustained and periodic signals from additional co-receptors are now being recognized as critical contributors to the activation of this pathway. Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway. We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units. We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR. We also review data that other TNFR molecules, such as CD40 (TNFRSF5), RANK (TNFRSF11A), FN14 (TNFRSF12A), TACI (TNFRSF13B), BAFFR (TNFRSF13C), and NGFR (TNFRSF16), contribute to the activation of this pathway in diverse cell types through a similar ability to recruit PI3K or Akt into their signaling complexes.