INT6 and Moe1 interact with Cdc48 to regulate proteolyis

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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.