| dc.description.abstract | Nonvisual arrestins (arrestin-2 and arrestin-3) regulate a wide range of signaling events, most notably when bound to active G protein-coupled receptors (GPCRs). Among the known effectors recruited by GPCR-bound arrestins are members of the mitogen-activated kinases (MAPKs) and members of the non-receptor tyrosine kinase Src family, which regulate cellular growth, proliferation, and stress response. Even though the role of arrestin in MAPK and Src signaling cascades has been extensively studied, the mechanisms of signal initiation and amplification remain unclear. A recent structure of inositol hexakisphosphate (IP6)-activated arrestin-3 at 2.4 Å demonstrated key conformational changes that occur upon arrestin activation in a receptor-independent manner. This structure supports prior studies that suggested arrestin can activate effectors independently of GPCR activation. It demonstrated that small molecules such as IP6 can fully activate arrestin-3 independently of GPCR interaction and elicit key structural changes within arrestin associated with activation. We hypothesize that arrestin can assume multiple active conformations to selectively bind distinct effectors and initiate receptor-independent downstream signaling. A major question in the field is how individual arrestin conformations can promote the scaffolding of signaling pathways, and how arrestin bias signaling toward a specific cellular outcome both in a receptor-dependent and receptor-independent manner. Therefore, understanding different effector interactions with nonvisual arrestins and how these interactions lead to downstream signaling would aid in elucidating this mechanism. My dissertation work aimed to increase our understanding of the molecular mechanism of arrestin-mediated signaling. For my research, I used the MAP kinase, p38α, and the non-receptor tyrosine member, Fgr, as the model systems to test our hypothesis using a combination of structural, biochemical, and cellular approaches. | |
