Gozani Or, Karuman Philip, Jones David R, Ivanov Dmitri, Cha James, Lugovskoy Alexey A, Baird Cheryl L, Zhu Hong, Field Seth J, Lessnick Stephen L, Villasenor Jennifer, Mehrotra Bharat, Chen Jian, Rao Vikram R, Brugge Joan S, Ferguson Colin G, Payrastre Bernard, Myszka David G, Cantley Lewis C, Wagner Gerhard, Divecha Nullin, Prestwich Glenn D, Yuan Junying
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2003 Jul 11;114(1):99-111. doi: 10.1016/s0092-8674(03)00480-x.
Phosphoinositides (PtdInsPs) play critical roles in cytoplasmic signal transduction pathways. However, their functions in the nucleus are unclear, as specific nuclear receptors for PtdInsPs have not been identified. Here, we show that ING2, a candidate tumor suppressor protein, is a nuclear PtdInsP receptor. ING2 contains a plant homeodomain (PHD) finger, a motif common to many chromatin-regulatory proteins. We find that the PHD fingers of ING2 and other diverse nuclear proteins bind in vitro to PtdInsPs, including the rare PtdInsP species, phosphatidylinositol 5-phosphate (PtdIns(5)P). Further, we demonstrate that the ING2 PHD finger interacts with PtdIns(5)P in vivo and provide evidence that this interaction regulates the ability of ING2 to activate p53 and p53-dependent apoptotic pathways. Together, our data identify the PHD finger as a phosphoinositide binding module and a nuclear PtdInsP receptor, and suggest that PHD-phosphoinositide interactions directly regulate nuclear responses to DNA damage.
磷酸肌醇（PtdInsPs）在细胞质信号转导途径中发挥关键作用。然而，它们在细胞核中的功能尚不清楚，因为尚未鉴定出PtdInsPs的特异性核受体。在此，我们表明ING2（一种候选肿瘤抑制蛋白）是一种核PtdInsP受体。ING2含有一个植物同源结构域（PHD）指，这是许多染色质调节蛋白共有的基序。我们发现ING2和其他多种核蛋白的PHD指在体外与PtdInsPs结合，包括罕见的PtdInsP种类磷脂酰肌醇5-磷酸（PtdIns(5)P）。此外，我们证明ING2的PHD指在体内与PtdIns(5)P相互作用，并提供证据表明这种相互作用调节ING2激活p53和p53依赖性凋亡途径的能力。总之，我们的数据确定PHD指为磷酸肌醇结合模块和核PtdInsP受体，并表明PHD-磷酸肌醇相互作用直接调节细胞核对DNA损伤的反应。
