Dvl3 translocates IPMK to the cell membrane in response to Wnt.
Dvl3 translocates IPMK to the cell membrane in response to Wnt.
复制标题
Dvl3 响应 Wnt 将 IPMK 易位至细胞膜。
DOI：
10.1016/j.cellsig.2012.08.009
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发表时间：
2012
影响因子：
4.8
通讯作者：
Wang,Hsien-yu
中科院分区：
文献类型：
--
作者：
Wang,Ying;Wang,Hsien-yu
Wnt 3a结合Frizzled-1和LRP 5/6共受体，最终激活发育中的Lef/Tcf敏感基因转录。肌醇多磷酸多激酶（IPMK）具有肌醇磷酸激酶和脂质肌醇激酶活性，在Wnt 3a调节其经典途径以及生理学上在AMPK信号传导中是必需的。在目前的报告中，我们表明，IPMK易位到细胞膜，在那里它的底物存在的高丰度，是专性的Wnt信号转导的功能。在Wnt 3a刺激后5分钟内，IPMK易位到细胞膜上。IPMK躲避到Dishevelled-3（Dvl 3）上需要PDZ结构域和Dvl 3的COOH末端富脯氨酰尾部。Wnt 3a刺激Dvl 3向细胞膜的移动，也将IPMK易位至细胞膜，以促进Frizzled 1的下游信号传导。缺失NH 2-末端可变区的IPMK突变体IPMKΔN不能转位到细胞膜上并传播经典信号。通过添加异戊二烯化的CAAX盒将IPMKΔN靶向回细胞膜，挽救了其在Wnt 3a下游信号传导中的功能。
Wnt3a binds Frizzled-1 and the LRP5/6 co-receptors, ultimately activating Lef/Tcf-sensitive gene transcription in development. Inositol polyphosphate multikinase, IPMK, which possesses inositol phosphate kinase and lipid inositol kinase activities, is essential in Wnt3a regulation of its canonical pathway as well as physiologically in AMPK signaling. In the current report we show that translocation of IPMK to the cell membrane, where its substrates exist in high abundance, is obligate to its function in Wnt signaling. Translocation of IPMK to the cell membrane occurs within 5min after Wnt3a stimulation. IPMK ducking onto Dishevelled-3 (Dvl3) requires a PDZ domain and the COOH-terminal prolyly-rich tail of Dvl3. Wnt3a-stimulates mobilization of Dvl3 to the cell membrane, translocating IPMK to the cell membrane also, to facilitate downstream signaling of Frizzled1. Deletion mutant of IPMK lacking the NH2-terminal variable region, IPMKΔN, fails to translocate to the cell membrane and to propagate canonical signaling. Targeting the IPMKΔN back to the cell membrane by addition of an isoprenylated CAAX box rescues its function in Wnt3a downstream signaling.