Regulation of alpha-arrestin ARRDC3 divergent tumor suppressor functions by ubiquitination
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Regulation of alpha-arrestin ARRDC3 divergent tumor suppressor functions by ubiquitination

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Abstract

-arrestins are a recently discovered family of mammalian proteins that function as trafficking and signaling adapters. Like -arrestins, which are structurally similar to -arrestins, -arrestins are known to regulate trafficking and signaling of G protein-coupled receptors (GPCRs). However, little is known about -arrestin functions in health and disease, as well as the molecular mechanisms that control their diverse functions. Thus far, the -arrestin ARRDC3 has been most closely linked to regulation of GPCR function as well as to breast cancer. ARRDC3 was demonstrated to act as a tumor suppressor in invasive breast cancer in vitro and in vivo, in large part due to regulation of GPCR trafficking and signaling. Yet, the molecular mechanisms which control ARRDC3 function are unknown, and are important in order to better understand -arrestin tumor suppressor function. Other arrestins are known to be regulated by post-translational modifications, including ubiquitination and phosphorylation, which suggests that ARRDC3 may be subject to similar regulatory mechanisms. In this dissertation, I explored the molecular mechanisms that control -arrestin ARRDC3 tumor suppressor function. We found that ARRDC3 has the potential to interact with multiple protein modifying enzymes, including ubiquitin ligases, kinases, phosphatases, and more. I then examined ubiquitination as a key regulator of ARRDC3 function. I found that ARRDC3 ubiquitination is mediated primarily by two proline-rich PPXY motifs in the ARRDC3 C-tail domain. The ARRDC4 PPXY motifs are critical for recruiting WWP2 E3 ubiquitin ligase and mediating ARRDC3 ubiquitination. Further, ubiquitination and the PPXY motifs are essential for ARRDC3 function in regulating GPCR trafficking and signaling. Additionally, ubiquitination and the PPXY motifs mediate ARRDC3 protein degradation and dictate ARRDC3 subcellular localization. My work demonstrates an important role for ubiquitination in regulating ARRDC3 function. Taken together, the studies summarized in this dissertation reveal a key mechanism by which ARRDC3 divergent functions are controlled.

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This item is under embargo until July 13, 2025.