Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells.
Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells.
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DOI：
10.4049/jimmunol.1002126
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Levings MK
中科院分区：
文献类型：
--
作者：
Patterson SJ;Han JM;Garcia R;Assi K;Gao T;O'Neill A;Newton AC;Levings MK
TCR具有降低的激活TCR下游的PI 3 K/Akt途径的能力，并且所产生的Akt的低活性是其发育和功能所必需的。然而，TcR不能有效激活Akt的分子基础仍然未知。我们发现，PH-结构域富含亮氨酸重复蛋白磷酸酶（PHLPP），脱磷酸化Akt，上调在Tclase，从而抑制Akt的激活。与常规T细胞相比，TCFs表达更高水平的PHLPP，并且PHLPP 1的敲低恢复了TCFs中TCR介导的Akt活化。与它们的高Akt活性一致，来自PHLPP 1-/-小鼠的TcR的抑制能力显著降低。此外，在PHLPP 1-/-小鼠中，诱导的TbR的发育受损。Akt的负调节因子PHLPP水平的增加提供了T细胞用于控制Akt途径的新机制，并且是TcB中Akt活性功能性必需降低的分子机制的第一个证据。
Tregs have a reduced capacity to activate the PI3K/Akt pathway downstream of the TCR, and the resulting low activity of Akt is necessary for their development and function. The molecular basis for the failure of Tregs to efficiently activate Akt, however, remained unknown. We show that PH-domain Leucine-rich-repeat Protein Phosphatase (PHLPP), which dephosphorylates Akt, is up-regulated in Tregs, thus suppressing Akt activation. Tregs expressed higher levels of PHLPP than conventional T cells and knock-down of PHLPP1 restored TCR-mediated activation of Akt in Tregs. Consistent with their high Akt activity, the suppressive capacity of Tregs from PHLPP1-/- mice was significantly reduced. Moreover, the development of induced Tregs was impaired in PHLPP1-/- mice. The increased level of Akt's negative regulator, PHLPP, provides a novel mechanism used by T cells to control the Akt pathway and the first evidence for a molecular mechanism underlying the functionally essential reduction of Akt activity in Tregs.
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影响因子：
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DOI：
10.1073/pnas.0800928105
发表时间：
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影响因子：
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作者：
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