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Regulation of N-formyl peptide receptor trafficking and signaling by arrestins

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/9336

Regulation of N-formyl peptide receptor trafficking and signaling by arrestins

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Title: Regulation of N-formyl peptide receptor trafficking and signaling by arrestins
Author: Wagener, Brant
Advisor(s): Prossnitz, Eric
Committee Member(s): Sklar, Larry
Hudson, Luarie
Hathaway, Helen
Department: University of New Mexico. Biomedical Sciences Graduate Program.
Subject(s): arrestin
FPR
apoptosis
signaling
trafficking
recycling
LC Subject(s): Peptides--Receptors
Cellular signal transduction
Protein-protein interactions
Degree Level: Doctoral
Abstract: This work focuses on how arrestin regulates trafficking and signaling of the N-formyl peptide receptor (FPR), a G protein-coupled receptor (GPCR). GPCRs are involved in almost all physiologic processes and numerous pathologic processes. There is an intimate relationship between GPCR trafficking and signaling that controls many cellular processes. However, the protein-protein interactions that control post-endocytic trafficking and signaling of GPCRs are poorly understood. Our previous reports demonstrated that three events take place upon FPR activation in the absence of arrestins: accumulation of FPR in the perinuclear recycling endosome, lack of FPR recycling and apoptosis. All of these phenotypes were rescued by reintroduction of arrestin-2 cDNA. We therefore hypothesized that 1) FPR trafficking and signaling defects were linked and causal and 2) specific regions of arrestin-2 regulate normal FPR trafficking and signaling. To address these hypotheses, we generated mutants of arrestin-2 that were previously described or changed regions of similar amino acids to alanine. We then screened these mutants for the ability to rescue FPR-mediated apoptosis. Subsequently, we examined the role of these arrestin mutants in FPR trafficking. We found that two arrestin-2 mutants demonstrated altered binding to adaptor protein (AP)-2. Furthermore, FPR recycling was inhibited in the presence of either arrestin-2 mutant or the absence of AP-2. We also examined the role of Src kinase in FPR trafficking and signaling and determined that Src kinase has two independent roles in FPR-arrestin-2 regulation: one that controls FPR trafficking and one that mediated FPR signaling. Finally, we found that different SH3-binding domains of arrestin-2 regulate FPR trafficking and signaling independently. An arrestin-2 mutant did not rescue FPR-mediated apoptosis, but did mediate normal FPR trafficking. These results indicate that FPR trafficking and signaling are coordinated processes, but may also be regulated independently. These studies have revealed novel aspects of arrestin-2 that regulate FPR signaling and trafficking. We hope they will serve as a model for the regulation of other GPCRs. Furthermore, we hope these data are used to create small molecule inhibitors to serve as experimental tools and chemotherapeutics to better understand and treat diseases caused by defects in GPCR trafficking and signaling.
Graduation Date: May 2009
URI: http://hdl.handle.net/1928/9336

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