INT6 and Moe1 interact with Cdc48 to regulate proteolyis

描述（由申请人提供）：INT基因的研究导致发现了非常重要的信号蛋白家族，并对理解肿瘤发生做出了重大贡献。 在INT基因中，INT 6的功能是最不清楚的。 本实验室利用INT 6在粟酒裂殖酵母中的同源基因yin 6进行了研究。 Yin 6通过正向调节蛋白酶体的组装/定位来调节有丝分裂进程（染色体分离和纺锤体动力学）。 我的总体目标是进一步了解Yin 6如何调节蛋白水解和有丝分裂。 我的研究集中在另一个保守的蛋白质Moe 1上，Yin 6直接与Moe 1结合。有趣的是，虽然Yin 6结合蛋白酶体，但Moe 1不结合，我们的初步数据表明Moe 1可以与蛋白质相互作用，这些蛋白质作为蛋白酶体的底物受体，例如Cdc 48，这是一种AAA ATP酶，是ERAD（内质网相关降解）过程中的关键组分，以及有丝分裂和纺锤体动力学。 该项目将测试Yin 6-Moe 1通过Meet与Cdc 48的结合连接底物选择和通过Yin 6与蛋白酶体的结合连接蛋白水解以促进蛋白降解的假设。 此外，我将测试这种机制是如何参与ERAD和/或有丝分裂纺锤体解体的调节。 因此，在目标1中，S.将研究粟酒裂殖酵母以证明该复合物在体内的形成。 在目标2中，这些相互作用在调节ERAD中的作用将进行生物化学和遗传学研究。最后，在Aim 3中，将检查Yin 6-Moe 1复合物与Cdc 48在调节有丝分裂纺锤体形成中的相互作用的作用。 这些研究的结果旨在更好地了解Int 6，Moe 1和Cdc 48如何参与肿瘤发生。

DESCRIPTION (provided by applicant): Studies of the INT genes have led to the discovery of families of very important signaling proteins, and contributed significantly to the understanding of tumorigenesis. Among the INT genes, the function of INT6 is the least understood. Our lab has studied INT6 by using its homolog yin6 in the model organism Schizosaccharomyces pombe. Yin6 regulates mitotic progression (chromosome segregation and spindle dynamics) by positively regulating the assembly/localization of the proteasome. My overall goal is to further understand how Yin6 regulates proteolysis and mitosis. My study centers on another conserved protein, Moe1, to which Yin6 binds directly. Intriguingly, while Yin6 binds the proteasome, Moe1 does not, and our preliminary data show that Moe1 can interact with proteins that act as substrate receptors for the proteasome, such as Cdc48, which is an AAA ATPase, a key component in a process called ERAD (Endoplasmic Reticulum Associated Degradation), as well as in mitosis and spindle dynamics. This project will test the hypothesis that the Yin6-Moe1 links substrate selection, via Meet's binding to Cdc48, and proteolysis, via Yin6's binding to the proteasome, to facilitate protein degradation. Furthermore, I will test how this mechanism is involved in the regulation of ERAD and/or mitotic spindle disassembly. Thus, in Aim 1, further physical interactions in S. pombe will be studied to prove the formation of the complex in vivo. In Aim 2, the role of these interactions in regulating ERAD will be studied biochemically and genetically. Lastly, in Aim3, a role for the interaction of the Yin6-Moe1 complex with Cdc48 in regulating the formation of the mitotic spindle will be examined. The results of these studies are intended to provide a better understanding of how Int6, Moe1 and Cdc48 may be involved in tumorigenesis.