G protein-coupled receptors (GPCRs) mediate hormonal control of numerous signaling pathways, many of which are dynamically regulated. At the level of the receptor, regulation can occur via inhibition of GPCR/G protein coupling (desensitization), redistribution of cell surface receptors (trafficking), or receptor degradation (down-regulation). Two protein families, GPCR kinases (GRKs) and arrestins, play a critical role in these processes. GRKs specifically phosphorylate the activated form of the receptor, which in turn promotes arrestin binding. Arrestin interaction has been directly linked to many processes including GPCR desensitization, trafficking, and G protein-independent signaling. In the initial period ofthe MERIT award, we focused on characterizing the role of arrestin interaction with other proteins and how such interactions mediate the biological effects of arrestins. In addition, we used biophysical approaches to better understand how arrestins mediate receptor trafficking. These studies have resulted in 14 peer-reviewed publications as well as 5 manuscripts in various stages of submission. In the MERIT award extension period, we propose to continue our work in four areas. The first will involve further characterizing the functional role of arrestin interactions with a number of target proteins that we have already identified including RCC2, API and PTEN. The second area involves correlating the functional and biological roles of arrestin interactions in cell lines and in C. elegans. A third area will involve the use of biophysical approaches to better understand the scaffolding properties of arrestins and how receptor binding regulates arrestin conformation and interaction. A final area that we plan to pursue involves characterizing the link between arrestins and two other protein families (Vps26 and a-arrestins) that appear to have structural similarities with the arrestins. Overall, our efforts will provide unique mechanistic insight into the biochemical, cellular and molecular function of arrestins and should prove important in understanding diseases where GPCR signaling defects are observed.

Public Health Relevance

Arrestins have a broad biological role in various organisms although relatively little is known about how the function of arrestins in cells correlates with the observed biology. Our proposed research will provide unique mechanistic insight into the biochemical, cellular and molecular function of arrestins and should prove important in understanding the biological function of arrestins and their role in disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Dunsmore, Sarah
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Thomas Jefferson University
Schools of Medicine
United States
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Kook, S; Zhan, X; Cleghorn, W M et al. (2014) Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death. Cell Death Differ 21:172-84
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2014) Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63-71
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2013) *-Arrestins and G protein-coupled receptor trafficking. Methods Enzymol 521:91-108
Bychkov, E R; Ahmed, M R; Gurevich, V V et al. (2011) Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder. Neurobiol Dis 44:248-58
Chen, X P; Yang, W; Fan, Y et al. (2010) Structural determinants in the second intracellular loop of the human cannabinoid CB1 receptor mediate selective coupling to G(s) and G(i). Br J Pharmacol 161:1817-34
Shankar, Haripriya; Michal, Allison; Kern, Ronald C et al. (2010) Non-visual arrestins are constitutively associated with the centrosome and regulate centrosome function. J Biol Chem 285:8316-29
Li, Guo; Shi, Ying; Huang, Haishan et al. (2010) Internalization of the human nicotinic acid receptor GPR109A is regulated by G(i), GRK2, and arrestin3. J Biol Chem 285:22605-18
Palmitessa, Aimee; Benovic, Jeffrey L (2010) Arrestin and the multi-PDZ domain-containing protein MPZ-1 interact with phosphatase and tensin homolog (PTEN) and regulate Caenorhabditis elegans longevity. J Biol Chem 285:15187-200
Huang, Haishan; He, Xiaobai; Deng, Xiaoyan et al. (2010) Bombyx adipokinetic hormone receptor activates extracellular signal-regulated kinase 1 and 2 via G protein-dependent PKA and PKC but ?-arrestin-independent pathways. Biochemistry 49:10862-72
Busillo, John M; Armando, Sylvain; Sengupta, Rajarshi et al. (2010) Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. J Biol Chem 285:7805-17

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