Role of membrane trafficking in Wnt signaling that regulates gastrulation

Rab GTP酶是细胞内膜运输的关键调节因子。我们试图阐明Rab GTP酶在非洲爪蟾原肠胚形成中的作用，并发现Rab 40（XRab 40）的非洲爪蟾同源物是正常原肠胚形成所必需的。XRab 40定位于高尔基体并与ElonginB/C和Cullin 5相互作用以形成泛素连接酶。XRab 40/XCullin 5协同作用并调节Rap 2 GT3的泛素化和定位。此外，XRab 40/XCullin 5通过Rap 2及其效应器Misshapen/Nck相互作用激酶（XMINK）调节Wnt途径中的关键信号分子Dishevelled的膜定位。XMINK与Dishevelled相互作用，并通过Wnt活化转移至质膜。我们提出了一个新的信号级联组成的XRab 40/XCullin 5，Rap 2和XMINK，这在非经典Wnt通路的调节中起着至关重要的作用。

Rab GTPases are key regulators of intracellular membrane trafficking. We sought to elucidate the roles of Rab GTPases in Xenopus gastrulation, and found that a Xenopus homolog of Rab40 (XRab40) is required for normal gastrulation. XRab40 is localized at the Golgi apparatus and interacts with ElonginB/C and Cullin5 to form a ubiquitin ligase. XRab40/XCullin5 functions cooperatively and regulates the ubiquitination and localization of Rap2 GTPase. Furthermore, XRab40/XCullin5 regulates the membrane localization of Dishevelled, a key signaling molecule in the Wnt pathway, through Rap2 and its effector Misshapen/Nck interacting kinase (XMINK). XMINK interacts with Dishevelled, and is translocated to the plasma membrane by Wnt activation. We propose a novel signaling cascade consisting of XRab40/XCullin5, Rap2 and XMINK, which plays a crucial role in the regulation of the noncanonical Wnt pathway.