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Catalytic activation of beta-arrestins allows novel trafficking and signaling functions

Abstract

This thesis examines the trafficking and signaling functions of beta-arrestins, a highly conserved class of proteins that are critical regulators of G protein coupled receptor function (GPCRs), a large family of seven-transmembrane signaling receptors. The introductory chapter provides an overview of GPCR biology and cell signaling, details the discovery of arrestins, presents the data leading to the canonical view of arrestin function, discusses a surge of recent structural data, and briefly describes the cell biological approaches used in this thesis. The 2nd chapter describes the role of each β-arrestin isoform in the signaling and trafficking of the β2 adrenergic receptor (β2AR) and elucidates a RAS-mediated pathway for ERK activation that is downstream of β2AR activation but independent of β-arrestins. Chapter 3 provides evidence for a novel mode of β-arrestin function termed ‘action at a distance’ in which β-arrestin can dissociate from its activating GPCR and activate ERK signaling pathways from clathrin-coated structures, providing evidence of an unprecedented mode of β-arrestin function. Chapter 4 elucidates the cellular mechanism of a catalytic activation cycle of β-arrestins that can explain the action at a distance behavior observed with both β-arrestin isoforms and diverse GPCR family members. Chapter 5 examines the role of β-arrestin catalytic activation in initiating arrestin-mediated signaling. Lastly, Chapter 6 summarizes the major new conceptual findings from the previous chapters, discusses these in the context of previously established results and dogma, and explores open questions for future study.

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