G protein-coupled receptors (GPCRs) mediate hormonal control of numerous signaling pathways, manyof 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 rolein 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, wefocused 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 understandhow arrestins mediate receptor trafficking. These studies have resulted in 14 peer-reviewed publications aswell 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 willinvolve further characterizing the functional role of arrestin interactions with a number of target proteins thatwe have already identified including RCC2, API and PTEN. The second area involves correlating thefunctional and biological roles of arrestin interactions in cell lines and in C. elegans. A third area will involvethe use of biophysical approaches to better understand the scaffolding properties of arrestins and howreceptor binding regulates arrestin conformation and interaction. A final area that we plan to pursue involvescharacterizing the link between arrestins and two other protein families (Vps26 and a-arrestins) that appearto have structural similarities with the arrestins. Overall, our efforts will provide unique mechanistic insightinto the biochemical, cellular and molecular function of arrestins and should prove important inunderstanding 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 thefunction of arrestins in cells correlates with the observed biology. Our proposed research will provide uniquemechanistic insight into the biochemical, cellular and molecular function of arrestins and should proveimportant in understanding the biological function of arrestins and their role in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM047417-18
Application #
7921783
Study Section
Special Emphasis Panel (NSS)
Program Officer
Dunsmore, Sarah
Project Start
1994-01-01
Project End
2016-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
18
Fiscal Year
2011
Total Cost
$392,501
Indirect Cost
Name
Thomas Jefferson University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Tian, Xufan; Irannejad, Roshanak; Bowman, Shanna L et al. (2016) The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor. J Biol Chem 291:14510-25
Carr 3rd, Richard; Benovic, Jeffrey L (2016) From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins. Biochem Soc Trans 44:555-61
Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) β-arrestin-biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16
Carr 3rd, Richard; Koziol-White, Cynthia; Zhang, Jie et al. (2016) Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms. Mol Pharmacol 89:94-104
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 β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63-71
Carr 3rd, Richard; Du, Yang; Quoyer, Julie et al. (2014) Development and characterization of pepducins as Gs-biased allosteric agonists. J Biol Chem 289:35668-84
Tian, Xufan; Kang, Dong Soo; Benovic, Jeffrey L (2014) β-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol 219:173-86
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2013) β-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

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