UCSF

This thesis addresses the endosomal sorting of the beta-2 adrenergic receptor (B2AR), a "typical" (family A) member of the large superfamily of seven-transmembrane signaling receptors, the G-protein coupled receptors (GPCRs). The introductory chapter provides background on the general importance of sorting in the cell, how sorting affects signaling receptors, models for protein sorting, a primer on sequence based sorting, and a brief explanation of the scientific approach I took in my thesis work. The 2nd chapter details findings on the role of ubiquitin and the ESCRT machinery in sorting of B2AR. We find that direct receptor ubiquitination plays no role in endosomal sorting of B2AR to the lysosome. Chapter 3 explores the role of actin in maintaining a subset of endosomal tubules which are important for B2AR recycling. In chapter 4, a direct interactor of the B2AR sorting sequence, SNX27, is identified and its role in recycling of B2AR is chronicled. Chapter 5 introduces the retromer complex as the endosomal sorting location for B2AR. Further, it elucidates the connectivity of SNX27 to the retromer and demonstrates a role for SNX27 in receptor entry into the retromer tubule. Lastly, Chapter 6 explores the results presented in the previous chapters, attempts to reconcile them with the "big picture," and suggests avenues for future study.