Regulation of signaling pathway by frizzled family and its biological significance.

卷曲家族对信号通路的调控及其生物学意义。

基本信息

批准号：
15570168
负责人：
YAO Ryoji
金额：
$ 2.37万
依托单位：
Japanese Foundation for Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570168/
关键词：
frizzled Wnt GOPC MAGI-3 Knockout mouse wnt knockout mouse Frizzled Ltap JNK

项目摘要

Serpentine receptor, frizzled, plays important roles in several signaling including Wnt canonical pathway. We have identified three frizzled interacting proteins (fzip) as binding partners for C-terminal cytoplasmic domain of frizzled proteins.Fzip-1 was a novel gene and was named GOPC. GOPC had a role in the vesicle transport of frizzled from the Golgi apparatus to the plasma membrane. Gene targeting of GOPC resulted in the failure of spermatogenesis, revealing its critical role for the vesicle transport from the Golgi apparatus to acrosome.Fzip-2 turned out to be identical to MAGI-3, a scaffold protein of membrane proteins. MAGI-3 specifically bound to frizzled-4 and 7 among mammalian frizzled family members. MAGI-3 also interacted with Ltap, a mouse PCP protein, and they formed ternary complex, which in turn regulated the JNK signaling.Fzip-3 was localized at centrosome as well as mitotic spindle in mitotic cells. Homozygous null mutants were embryonic lethal, while homozygous mutants of hypomorphic allele resulted in neonatal death, indicating its dose-dependent roles in mouse embryogenesis. Fzip-3 depleted MEFs showed abnormal mitosis, which seemed to be the primary defects in mutant mouse. Finally, we have established conditional mice and these mice provide us the opportunity to investigate function of fzip-3 in adult mouse.

蛇纹石受体（卷曲）在包括Wnt典型途径在内的多种信号传导中起着重要作用。我们已经将三种毛躁相互作用的蛋白（FZIP）确定为卷曲蛋白的C末端细胞质结构域的结合伴侣。FZIP-1是一种新型基因，被称为GOPC。 GOPC在从高尔基体到质膜的卷曲囊泡运输中发挥了作用。 GOPC的基因靶向导致精子发生失败，从而揭示了其在囊泡转运从高尔基体到ACROSOMOS的囊泡转运的关键作用。FZIP-2证明与Magi-3相同，Magi-3是膜蛋白的支架蛋白。 MAGI-3在哺乳动物毛躁的家庭成员中特别绑定到毛躁4和7。 MAGI-3还与小鼠PCP蛋白LTAP相互作用，并形成三元复合物，进而调节JNK信号传导。FZIP-3位于中心体和有丝分裂细胞中的有丝分裂纺锤体。纯合无零突变体是胚胎致死的，而型型型型型纯态突变体导致新生儿死亡，表明其剂量依赖性在小鼠胚胎发生中的作用。 FZIP-3耗尽的MEF表现出异常有丝分裂，这似乎是突变小鼠的主要缺陷。最后，我们建立了条件小鼠，这些小鼠为我们提供了研究FZIP-3在成年小鼠中的功能的机会。