Leslie N R, Batty I H, Maccario H, Davidson L, Downes C P
Division of Molecular Physiology, College of Life Sciences, University of Dundee, James Black Centre, Dundee, Scotland, UK.
Oncogene. 2008 Sep 18;27(41):5464-76. doi: 10.1038/onc.2008.243.
The PTEN tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (PI3K)-dependent signalling by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (PtdInsP(3)). Here, we discuss the concept of PTEN as an 'interfacial enzyme', which exists in a high activity state when bound transiently at membrane surfaces containing its substrate and other acidic lipids, such as PtdIns(4,5)P(2) and phosphatidylserine (PtdSer). This mechanism ensures that PTEN functions in a spatially restricted manner, and may explain its involvement in forming the gradients of PtdInsP(3), which are necessary for generating and/or sustaining cell polarity during motility, in developing neurons and in epithelial tissues. Coordinating PTEN activity with alternative mechanisms of PtdInsP(3) metabolism, by the tightly regulated SHIP 5-phoshatases, synthesizing the independent second messenger PtdIns(3,4)P(2), may also be important for cellular polarization in some cell types. Superimposed on this interfacial mechanism are additional post-translational regulatory processes, which generally act to reduce PTEN activity. Oxidation of the active site cysteine residue by reactive oxygen species and phosphorylation of serine/threonine residues at sites in the C-terminus of the protein inhibit PTEN. These phosphorylation sites also appear to play a role in regulating both stability and localization of PTEN, as does ubiquitination of PTEN. Because genetic studies in mice show that the level of expression of PTEN in an organism profoundly influences tumour susceptibility, factors that regulate PTEN, localization, activity and turnover should be important in understanding its biological functions as a tumour suppressor.
PTEN肿瘤抑制因子是一种脂质和蛋白质磷酸酶，它通过使磷脂酰肌醇3,4,5-三磷酸（PtdInsP(3)）去磷酸化来抑制磷酸肌醇3-激酶（PI3K）依赖性信号传导。在此，我们讨论PTEN作为一种“界面酶”的概念，当它短暂结合在含有其底物和其他酸性脂质（如磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P(2)）和磷脂酰丝氨酸（PtdSer））的膜表面时，处于高活性状态。这种机制确保PTEN以空间受限的方式发挥作用，并且可能解释了它参与形成PtdInsP(3)梯度，这对于在运动、发育中的神经元和上皮组织中产生和/或维持细胞极性是必需的。通过严格调控的SHIP 5-磷酸酶将PTEN活性与PtdInsP(3)代谢的其他机制相协调，合成独立的第二信使磷脂酰肌醇-3,4-二磷酸（PtdIns(3,4)P(2)），对于某些细胞类型中的细胞极化也可能很重要。叠加在这种界面机制之上的是其他翻译后调控过程，这些过程通常起到降低PTEN活性的作用。活性位点半胱氨酸残基被活性氧氧化以及蛋白质C末端位点的丝氨酸/苏氨酸残基磷酸化会抑制PTEN。这些磷酸化位点似乎在调节PTEN的稳定性和定位方面也发挥作用，PTEN的泛素化也是如此。因为对小鼠的遗传学研究表明，生物体中PTEN的表达水平深刻影响肿瘤易感性，所以调节PTEN的定位、活性和周转的因素对于理解其作为肿瘤抑制因子的生物学功能应该很重要。
