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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.

丝氨酸蛋白酶受体是一种卷曲蛋白，在包括Wnt经典信号通路在内的多种信号转导中起重要作用。我们已经鉴定了三个卷曲蛋白相互作用蛋白（fzip），其中Fzip-1是一个新基因，命名为GOPC。GOPC参与了卷曲蛋白从高尔基体向质膜的囊泡运输。GOPC的基因打靶导致精子发生失败，揭示了GOPC在囊泡从高尔基体向顶体转运中的关键作用。MAGI-3特异性结合哺乳动物卷曲蛋白家族成员中的卷曲蛋白-4和卷曲蛋白-7。MAGI-3还与小鼠PCP蛋白Ltap相互作用形成三元复合物，进而调节JNK信号通路。Fzip-3定位于有丝分裂细胞的中心体和纺锤体。纯合无效突变体可导致胚胎死亡，而亚纯合等位基因突变体可导致新生儿死亡，表明其在小鼠胚胎发生中的作用具有剂量依赖性。Fzip-3缺失的MEFs表现出异常的有丝分裂，这似乎是突变小鼠的主要缺陷。最后，我们建立了条件小鼠，这些小鼠为我们研究fzip-3在成年小鼠中的功能提供了机会。