PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms
PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms
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DOI：
10.1016/j.molcel.2007.02.017
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发表时间：
2007-03-23
期刊：
影响因子：
16
通讯作者：
Newton, Alexandra C.
中科院分区：
文献类型：
--
作者：
Brognard, John;Sierecki, Emma;Newton, Alexandra C.
AKT/蛋白激酶B控制细胞的生长、增殖和存活。我们最近发现了一种新的磷酸酶PHLPP，它是PH域富含亮氨酸的重复蛋白磷酸酶，通过直接去磷酸化和失活Akt来终止Akt信号转导。在这里，我们描述了第二个家族成员，PHLPP2，它也可以使Akt失活，抑制细胞周期进程，并促进细胞凋亡。这些磷酸酶控制Akt信号的幅度：任何一种亚型的缺失都会使激动剂诱导的Akt磷酸化程度增加近两个数量级。虽然PHLPP1和PHLPP2都去磷酸化Akt上的相同残基(疏水磷酸化基序)，但它们通过调节不同的Akt亚型来不同地终止Akt信号。基因敲除研究表明，PHLPP1通过Akt2特异性地调节Hdm2和GSK-3α的磷酸化，而PHLPP2通过AKT3特异性地调节p27的磷酸化。我们的数据揭示了一种机制，通过特定PHLPP亚型对特定Akt亚型的差异失活来选择性地终止Akt信号通路。
Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis. These phosphatases control the amplitude of Akt signaling: depletion of either isoform increases the magnitude of agonist-evoked Akt phosphorylation by almost two orders of magnitude. Although PHLPP1 and PHLPP2 both dephosphorylate the same residue (hydrophobic phosphorylation motif) on Akt, they differentially terminate Akt signaling by regulating distinct Akt isoforms. Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3 alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3. Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms.