Carricaburu Valerie, Lamia Katja A, Lo Elizabeth, Favereaux Laetitia, Payrastre Bernard, Cantley Lewis C, Rameh Lucia E
Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9867-72. doi: 10.1073/pnas.1734038100. Epub 2003 Aug 1.
Phosphatidylinositol-5-phosphate (PI-5-P) is a newly identified phosphoinositide with characteristics of a signaling lipid but no known cellular function. PI-5-P levels are controlled by the type II PI-5-P 4-kinases (PIP4K IIs), a family of kinases that converts PI-5-P into phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2). The PI-5-P pathway is an alternative route for PI-4,5-P2 synthesis as the bulk of this lipid is generated by the canonical pathway in which phosphatidylinositol-4-phosphate (PI-4-P) is the intermediate. Here we examined the effect of activation of the PI-5-P pathway on phosphoinositide 3-kinase (PI3K) signaling by expressing PIP4K II beta in cells that lack this enzyme. Although PIP4K II generates PI-4,5-P2, a substrate for PI3K, expression of this enzyme reduced rather than increased phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) levels in cells stimulated with insulin or cells expressing activated PI3K. This reduction in PI-3,4,5-P3 levels resulted in decreased activation of the downstream protein kinase, Akt/PKB. Consistent with these results, expression of IpgD, a bacterial phosphatase that converts PI-4,5-P2 to PI-5-P, resulted in Akt activation, and this effect was partially reversed by PIP4K II beta. PIP4K II beta expression did not impair insulin-dependent association of PI3K with insulin receptor substrate 1 (IRS1) but abbreviated Akt activation, indicating that PIP4K II regulates PI-3,4,5-P3 degradation rather than synthesis. These data support a model in which the PI-5-P pathway controls insulin signaling that leads to Akt activation by regulating a PI-3,4,5-P3 phosphatase.
5-磷酸磷脂酰肌醇（PI-5-P）是一种新发现的磷酸肌醇，具有信号脂质的特征，但尚无已知的细胞功能。PI-5-P的水平由II型PI-5-P 4-激酶（PIP4K IIs）控制，这是一类将PI-5-P转化为磷脂酰肌醇-4,5-二磷酸（PI-4,5-P2）的激酶家族。PI-5-P途径是PI-4,5-P2合成的一条替代途径，因为这种脂质的大部分是通过经典途径产生的，在经典途径中磷脂酰肌醇-4-磷酸（PI-4-P）是中间体。在这里，我们通过在缺乏这种酶的细胞中表达PIP4K IIβ来研究PI-5-P途径的激活对磷酸肌醇3-激酶（PI3K）信号传导的影响。尽管PIP4K II产生PI-4,5-P2（PI3K的一种底物），但该酶的表达降低而非增加了用胰岛素刺激的细胞或表达活化PI3K的细胞中的磷脂酰肌醇-3,4,5-三磷酸（PI-3,4,5-P3）水平。PI-3,4,5-P3水平的这种降低导致下游蛋白激酶Akt/PKB的活化减少。与这些结果一致，将PI-4,5-P2转化为PI-5-P的细菌磷酸酶IpgD的表达导致Akt活化，并且这种作用被PIP4K IIβ部分逆转。PIP4K IIβ的表达不损害PI3K与胰岛素受体底物1（IRS1）的胰岛素依赖性结合，但缩短了Akt活化，表明PIP4K II调节PI-3,4,5-P3的降解而非合成。这些数据支持了一个模型，即PI-5-P途径通过调节一种PI-3,4,5-P3磷酸酶来控制导致Akt活化的胰岛素信号传导。
