Hribal Marta Letizia, Mancuso Elettra, Spiga Rosangela, Mannino Gaia Chiara, Fiorentino Teresa Vanessa, Andreozzi Francesco, Sesti Giorgio
a Department of Medical and Surgical Sciences , University Magna Græcia of Catanzaro , Catanzaro , Italy.
Expert Opin Ther Targets. 2016 Jun;20(6):663-75. doi: 10.1517/14728222.2016.1130822. Epub 2016 Jan 11.
Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs), originally identified as Akt kinase hydrophobic motif specific phosphatases, have subsequently been shown to regulate several molecules recurring within the insulin signaling pathway. This observation suggests that PHLPP phosphatases may have a clinically relevant role in the pathogenesis of insulin resistance-related diseases and may thus represent suitable targets for the treatment of these conditions.
The literature pertaining to PHLPPs substrates is reviewed herein, along with information on the molecular players involved in regulating the activity and expression of PHLPP phosphatases. In the present review, knowledge of genetic variants in the genes that encode for PHLPP isozymes and the surrounding regulatory regions is also summarized. In addition, data from the studies addressing the role of PHLPPs in insulin resistance-related disorders and from those investigating the possibility to manipulate these phosphatases for therapeutic purposes are presented.
A number of issues should be resolved before PHLPPs are pursued as therapeutic targets including: the mechanisms regulating the specificity of PHLPP isozymes; the possibility of differentially regulating PHLPP family members and the possible impact of PHLPPs modulation on the risk of cancer.
普列克底物蛋白同源结构域富含亮氨酸重复序列蛋白磷酸酶（PHLPPs）最初被鉴定为Akt激酶疏水基序特异性磷酸酶，随后被证明可调节胰岛素信号通路中反复出现的几种分子。这一观察结果表明，PHLPP磷酸酶可能在胰岛素抵抗相关疾病的发病机制中具有临床相关作用，因此可能是治疗这些疾病的合适靶点。
本文综述了与PHLPPs底物相关的文献，以及有关调节PHLPP磷酸酶活性和表达的分子机制的信息。在本综述中，还总结了编码PHLPP同工酶的基因及其周围调控区域的遗传变异知识。此外，还介绍了关于PHLPPs在胰岛素抵抗相关疾病中的作用以及研究操纵这些磷酸酶用于治疗目的可能性的研究数据。
在将PHLPPs作为治疗靶点之前，有许多问题需要解决，包括：调节PHLPP同工酶特异性的机制；差异调节PHLPP家族成员的可能性以及PHLPPs调节对癌症风险的可能影响。
