Molecular Cell:發現天然腫瘤抑制蛋白PHLPP的突變體

    基於實驗室在2005年的研究成果，加州大學醫學院的研究者如今識別出了可作為治療糖尿病、心臟病和神經系統疾病的靶點酶（enzyme）的另外兩個突變體。此項研究是由藥理學教授Alexandra  C.  Newton和他的同事一起完成的，文章發表在最新一期的《分子細胞》（Molecular  Cell）雜誌上。

    之前，同樣由Newton所做的研究成果也發表在《分子細胞》雜誌上。在那篇文章中，作者發現了一種酶——PHLPP（PH  domain  Leucine-rich  repeat  Protein  Phosphatase)，該酶可以關閉  Akt/蛋白激酶B（該蛋白調控著細胞生長、增殖和生存）的信號。

    新的研究工作描述了該家族的第二位成員：PHLPP2。PHLPP2同樣可以讓Akt失活，從而抑制細胞周期，促使細胞死亡。但是，PHLPP1和PHLPP2調控著三種不同的疾病通路：PHLPP1在糖尿病治療中起著重要的作用，PHLPP2在治療心臟病和神經系統疾病上可能有著重要應用價值。

部分英文原文：
Molecular Cell, Vol 25, 917-931, 23 March 2007

Article

PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms

John Brognard,1,2 Emma Sierecki,1 Tianyan Gao,1,3 and Alexandra C. Newton1,

1 Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
2 Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA

Corresponding author
Alexandra C. Newton
[e-mail]

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-3α 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.

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