Turning off AKT: PHLPP as a drug target.
Turning off AKT: PHLPP as a drug target.
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关闭 AKT：PHLPP 作为药物靶点。
DOI：
10.1146/annurev-pharmtox-011112-140338
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发表时间：
2014
影响因子：
12.5
通讯作者：
Trotman LC
中科院分区：
文献类型：
--
作者：
Newton AC;Trotman LC
精确控制蛋白激酶催化的蛋白磷酸化和蛋白磷酸酶催化的蛋白去磷酸化之间的平衡对细胞稳态至关重要。这种平衡的放松会导致病理生理状态，导致癌症、心脏病和糖尿病等疾病。控制细胞生长、细胞存活的通路组分的异常磷酸化在癌症中尤为普遍。在这些途径中，研究最多的肿瘤抑制因子之一是脂质磷酸酶PTEN，它使脂质第二信使磷脂酰肌醇-3,4,5-三磷酸（PIP3）去磷酸化，从而阻止致癌激酶AKT的激活。2005年，一个蛋白磷酸酶家族的发现，其成员直接使AKT去磷酸化和失活，引入了一种新的磷脂酰肌醇-3激酶（PI3K）致癌途径的负调控因子。PH结构域富亮氨酸重复蛋白磷酸酶（PHLPP）同工酶包括一个新的肿瘤抑制家族，其两个成员，PHLPP1和PHLPP2，在前列腺等癌症中与PTEN一样经常被删除。因此，PHLPP是一种抑制致癌途径的新型治疗靶点，也是一种潜在的候选生物标志物，可以对患者进行分层，以便进行适当的靶向治疗。本文讨论了PHLPP在终止AKT信号通路中的作用以及药物干预如何影响这一途径。
Precise control of the balance between protein phosphorylation, catalyzed by protein kinases, and protein dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states, driving diseases such as cancer, heart disease, and diabetes, among many others. Aberrant phosphorylation of components of the pathways that control cell growth cell survival are particularly prevalent in cancer. One of the most studied tumor suppressors in these pathways is the lipid phosphatase, PTEN, which dephosphorylates the lipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), thus preventing activation of the oncogenic kinase AKT. In 2005, the discovery of a family of protein phosphatases whose members directly dephosphorylate and inactivate AKT introduced a new negative regulator of the phosphatidylinositol-3-kinase (PI3K) oncogenic pathway. PH domain Leucine-rich repeat Protein Phosphatase (PHLPP) isozymes comprise a novel tumor suppressor family whose two members, PHLPP1 and PHLPP2, are deleted as frequently as PTEN in cancers such as those of the prostate. PHLPP is thus a novel therapeutic target to suppress oncogenic pathways and is a potential candidate biomarker to stratify patients for the appropriate targeted therapeutics. This review discusses the role of PHLPP in terminating AKT signaling and how pharmacological intervention would impact this pathway.
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影响因子：
50.3
作者：
Chen M;Pratt CP;Zeeman ME;Schultz N;Taylor BS;O'Neill A;Castillo-Martin M;Nowak DG;Naguib A;Grace DM;Murn J;Navin N;Atwal GS;Sander C;Gerald WL;Cordon-Cardo C;Newton AC;Carver BS;Trotman LC
通讯作者：
Trotman LC
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
16
作者：
Brognard, John;Sierecki, Emma;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.
影响因子：
15.9
作者：
Alimonti, Andrea;Nardella, Caterina;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
6.3
作者：
Chen, Bo;Van Winkle, Jessica A.;Purcell, Nicole H.
通讯作者：
Purcell, Nicole H.