Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco, San Francisco, CA 94158, USA.
Sci Signal. 2012 Jun 19;5(229):ra44. doi: 10.1126/scisignal.2003111.
Phosphatidylinositol 4,5-bisphosphate (PIP₂) is best known as a plasma membrane-bound regulatory lipid. Although PIP₂ and phosphoinositide-modifying enzymes coexist in the nucleus, their nuclear roles remain unclear. We showed that inositol polyphosphate multikinase (IPMK), which functions both as an inositol kinase and as a phosphoinositide 3-kinase (PI3K), interacts with the nuclear receptor steroidogenic factor 1 (SF-1) and phosphorylates its bound ligand, PIP₂. In vitro studies showed that PIP₂ was not phosphorylated by IPMK if PIP₂ was displaced or blocked from binding to the large hydrophobic pocket of SF-1 and that the ability to phosphorylate PIP₂ bound to SF-1 was specific to IPMK and did not occur with type 1 p110 PI3Ks. IPMK-generated SF-1-PIP₃ (phosphatidylinositol 3,4,5-trisphosphate) was dephosphorylated by the lipid phosphatase PTEN. Consistent with the in vitro activities of IPMK and PTEN on SF-1-PIP(n), SF-1 transcriptional activity was reduced by silencing IPMK or overexpressing PTEN. This ability of lipid kinases and phosphatases to directly remodel and alter the activity of a non-membrane protein-lipid complex establishes a previously unappreciated pathway for promoting lipid-mediated signaling in the nucleus.
磷脂酰肌醇 4,5-二磷酸（PIP₂）作为一种质膜结合的调节性脂质而广为人知。尽管 PIP₂ 和磷酸肌醇修饰酶共同存在于核内，但它们的核内作用尚不清楚。我们发现，肌醇多磷酸激酶（IPMK）既具有肌醇激酶的功能，又具有磷酸肌醇 3-激酶（PI3K）的功能，它与核受体甾体生成因子 1（SF-1）相互作用，并磷酸化其结合的配体 PIP₂。体外研究表明，如果 PIP₂ 被置换或阻止与 SF-1 的大疏水性口袋结合，IPMK 不会使 PIP₂磷酸化，并且与 SF-1 结合的 PIP₂ 的磷酸化能力是 IPMK 特有的，不会与 1 型 p110 PI3K 发生。IPMK 生成的 SF-1-PIP₃（磷脂酰肌醇 3,4,5-三磷酸）被脂质磷酸酶 PTEN 去磷酸化。与 IPMK 和 PTEN 在 SF-1-PIP(n)上的体外活性一致，沉默 IPMK 或过表达 PTEN 均可降低 SF-1 转录活性。这种脂质激酶和磷酸酶直接重塑和改变非膜蛋白-脂质复合物活性的能力，为促进核内脂质介导的信号传递建立了一条以前未被重视的途径。
