The Sec14-like phosphatidylinositol transfer proteins Sec1413/SEC14L2 act as GTPase proteins to mediate Wnt/Ca2+ signaling
The Sec14-like phosphatidylinositol transfer proteins Sec1413/SEC14L2 act as GTPase proteins to mediate Wnt/Ca2+ signaling
复制标题
Sec14 样磷脂酰肌醇转移蛋白 Sec1413/SEC14L2 作为 GTPase 蛋白介导 Wnt/Ca2 信号传导
DOI：
10.7554/elife.26362
复制
发表时间：
2017-05-02
期刊：
影响因子：
7.7
通讯作者：
Jia, Shunji
中科院分区：
文献类型：
--
作者：
Gong, Bo;Shen, Weimin;Jia, Shunji
非经典Wnt/Ca 2+信号通路在胚胎发育、组织形成和疾病中起着重要作用。然而，目前还不清楚Wnt配体刺激的G蛋白偶联受体Frizzled如何激活磷脂酶以释放钙。在这里，我们报告，斑马鱼/人磷脂酰肌醇转移蛋白SEC 1413/SEC 14 L2作为GTdR蛋白，将Wnt信号从Frizzled转换为磷脂酶C（PLC）。sec 1413的缺失减弱了Wnt/Ca 2+响应活性，并导致斑马鱼胚胎的会聚和延伸（CE）缺陷。哺乳动物细胞中的生化分析表明，Sec 1413-GDP与Frizzled和Dishevelled形成复合物; Frizzled的Wnt配体结合诱导Sec 1413易位到质膜;然后Sec 1413-GTP结合并激活磷脂酶C δ 4a（Plc delta 4a）;随后，Plc delta 4a启动磷脂酰肌醇-4，5-二磷酸（PIP 2）信号传导，最终刺激钙释放。此外，Plc delta 4a可以作为GTP酶激活蛋白，加速Sec 1413结合的GTP水解为GDP。我们的数据提供了一个新的见解GTdR蛋白偶联的Wnt/Ca 2+信号转导。
The non-canonical Wnt/Ca2+ signaling pathway plays important roles in embryonic development, tissue formation and diseases. However, it is unclear how the Wnt ligand-stimulated, G protein-coupled receptor Frizzled activates phospholipases for calcium release. Here, we report that the zebrafish/human phosphatidylinositol transfer protein Sec1413/SEC14L2 act as GTPase proteins to transduce Wnt signals from Frizzled to phospholipase C (PLC). Depletion of sec1413 attenuates Wnt/Ca2+ responsive activity and causes convergent and extension (CE) defects in zebrafish embryos. Biochemical analyses in mammalian cells indicate that Sec1413-GDP forms complex with Frizzled and Dishevelled; Wnt ligand binding of Frizzled induces translocation of Sec1413 to the plasma membrane; and then Sec1413-GTP binds to and activates phospholipase C delta 4a (Plc delta 4a); subsequently, Plc delta 4a initiates phosphatidylinositol-4,5-bisphosphate (PIP2) signaling, ultimately stimulating calcium release. Furthermore, Plc delta 4a can act as a GTPase-activating protein to accelerate the hydrolysis of Sec1413-bound GTP to GDP. Our data provide a new insight into GTPase protein-coupled Wnt/Ca2+ signaling transduction.