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Review
, 76 (22), 4413-4421

Plethora of Functions Packed Into 45 kDa Arrestins: Biological Implications and Possible Therapeutic Strategies

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Review

Plethora of Functions Packed Into 45 kDa Arrestins: Biological Implications and Possible Therapeutic Strategies

Vsevolod V Gurevich et al. Cell Mol Life Sci.

Abstract

Mammalian arrestins are a family of four highly homologous relatively small ~ 45 kDa proteins with surprisingly diverse functions. The most striking feature is that each of the two non-visual subtypes can bind hundreds of diverse G protein-coupled receptors (GPCRs) and dozens of non-receptor partners. Through these interactions, arrestins regulate the G protein-dependent signaling by the desensitization mechanisms as well as control numerous signaling pathways in the G protein-dependent or independent manner via scaffolding. Some partners prefer receptor-bound arrestins, some bind better to the free arrestins in the cytoplasm, whereas several show no apparent preference for either conformation. Thus, arrestins are a perfect example of a multi-functional signaling regulator. The result of this multi-functionality is that reduction (by knockdown) or elimination (by knockout) of any of these two non-visual arrestins can affect so many pathways that the results are hard to interpret. The other difficulty is that the non-visual subtypes can in many cases compensate for each other, which explains relatively mild phenotypes of single knockouts, whereas double knockout is lethal in vivo, although cultured cells lacking both arrestins are viable. Thus, deciphering the role of arrestins in cell biology requires the identification of specific signaling function(s) of arrestins involved in a particular phenotype. This endeavor should be greatly assisted by identification of structural elements of the arrestin molecule critical for individual functions and by the creation of mutants where only one function is affected. Reintroduction of these biased mutants, or introduction of monofunctional stand-alone arrestin elements, which have been identified in some cases, into double arrestin-2/3 knockout cultured cells, is the most straightforward way to study arrestin functions. This is a laborious and technically challenging task, but the upside is that specific function of arrestins, their timing, subcellular specificity, and relations to one another could be investigated with precision.

Keywords: Arrestin; GPCR; MAP kinases; Protein engineering; Receptor specificity; Signaling.

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References

    1. Science. 1999 Jan 29;283(5402):655-61 - PubMed

References

    1. Trends Biochem Sci. 2018 Jun;43(6):412-423 - PubMed

References

    1. Structure. 2003 Sep;11(9):1037-42 - PubMed

References

    1. BMC Evol Biol. 2017 Jul 6;17(1):163 - PubMed

References

    1. FEBS Lett. 1993 Nov 15;334(2):203-9 - PubMed

References

    1. PLoS One. 2011;6(12):e28723 - PubMed

References

    1. Science. 1996 Jan 19;271(5247):363-6 - PubMed

References

    1. J Neurosci. 2010 Jul 14;30(28):9381-91 - PubMed

References

    1. J Biol Chem. 1999 Mar 12;274(11):6831-4 - PubMed

References

    1. J Biol Chem. 1993 Jul 25;268(21):15640-8 - PubMed

References

    1. J Mol Biol. 2006 Dec 15;364(5):955-63 - PubMed

References

    1. EMBO J. 2007 Mar 21;26(6):1726-36 - PubMed

References

    1. J Immunol. 1977 Dec;119(6):1949-58 - PubMed

References

    1. Science. 2000 Nov 24;290(5496):1574-7 - PubMed

References

    1. Pharmacol Rev. 2017 Jul;69(3):256-297 - PubMed

References

    1. J Biol Chem. 2006 Jun 30;281(26):18081-9 - PubMed

References

    1. J Biol Chem. 2012 Jun 1;287(23):19653-64 - PubMed

References

    1. J Biol Chem. 2007 Dec 21;282(51):36971-9 - PubMed

References

    1. J Biol Chem. 1995 Oct 20;270(42):24782-9 - PubMed

References

    1. J Biol Chem. 2012 Aug 24;287(35):29495-505 - PubMed

References

    1. Crit Rev Biochem Mol Biol. 2015;50(5):440-52 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1825-30 - PubMed

References

    1. J Biol Chem. 2006 Feb 10;281(6):3458-62 - PubMed

References

    1. J Mol Biol. 2005 Dec 16;354(5):1069-80 - PubMed

References

    1. J Biol Chem. 1994 Feb 11;269(6):4613-9 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12011-6 - PubMed

References

    1. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3712-7 - PubMed

References

    1. Trends Pharmacol Sci. 2018 Jul;39(7):672-684 - PubMed

References

    1. Protein Sci. 1994 Dec;3(12):2428-34 - PubMed

References

    1. Nature. 1996 Oct 3;383(6599):447-50 - PubMed

References

    1. J Biol Chem. 2011 Jul 8;286(27):24288-99 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3125-8 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):942-7 - PubMed

References

    1. Genome Biol. 2006;7(9):236 - PubMed

References

    1. Mol Pharmacol. 1997 Jan;51(1):161-9 - PubMed

References

    1. J Mol Biol. 2010 Jan 8;395(1):42-54 - PubMed

References

    1. J Biol Chem. 2004 Jan 9;279(2):1262-8 - PubMed

References

    1. J Biol Chem. 2000 Dec 1;275(48):37679-85 - PubMed

References

    1. Nat Commun. 2014 Sep 10;5:4801 - PubMed

References

    1. Sci Signal. 2018 Sep 25;11(549): - PubMed

References

    1. J Biol Chem. 1999 Apr 16;274(16):10677-80 - PubMed

References

    1. J Biol Chem. 1999 Apr 23;274(17):11451-4 - PubMed

References

    1. J Biol Chem. 1992 Sep 5;267(25):17882-90 - PubMed

References

    1. J Biol Chem. 2009 Apr 24;284(17):11425-35 - PubMed

References

    1. Cell Signal. 2014 Jul;26(7):1523-31 - PubMed

References

    1. Science. 1990 Jun 22;248(4962):1547-50 - PubMed

References

    1. PLoS One. 2019 Mar 15;14(3):e0213792 - PubMed

References

    1. Biochemistry. 2011 Dec 6;50(48):10520-9 - PubMed

References

    1. J Biol Chem. 1998 Dec 18;273(51):34616-22 - PubMed

References

    1. Biochemistry. 2011 Aug 16;50(32):6951-8 - PubMed

References

    1. J Biol Chem. 1993 Jun 5;268(16):11628-38 - PubMed

References

    1. J Biol Chem. 2002 Mar 15;277(11):9043-8 - PubMed

References

    1. Cell Signal. 2014 Apr;26(4):766-76 - PubMed

References

    1. Cell Signal. 2017 Aug;36:98-107 - PubMed

References

    1. Pharmacol Ther. 2012 Jan;133(1):40-69 - PubMed

References

    1. Structure. 2001 Sep;9(9):869-80 - PubMed

References

    1. Nature. 2013 May 2;497(7447):137-41 - PubMed

References

    1. J Biol Chem. 1992 Apr 25;267(12):8558-64 - PubMed

References

    1. FEBS Lett. 1984 Oct 29;176(2):473-8 - PubMed

References

    1. J Biol Chem. 1995 Jan 13;270(2):720-31 - PubMed

References

    1. Cell Signal. 2013 Nov;25(11):2155-62 - PubMed

References

    1. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1174-8 - PubMed

References

    1. J Biol Chem. 1991 Oct 5;266(28):18649-54 - PubMed

References

    1. Sci Signal. 2017 Jun 20;10(484): - PubMed

References

    1. Nat Commun. 2017 Nov 10;8(1):1427 - PubMed

References

    1. J Biol Chem. 2013 Dec 27;288(52):37332-42 - PubMed

References

    1. Handb Exp Pharmacol. 2014;219:205-23 - PubMed

References

    1. Pharmacol Ther. 2006 Jun;110(3):465-502 - PubMed

References

    1. J Biol Chem. 2006 Apr 7;281(14):9765-72 - PubMed

References

    1. Biochemistry. 1995 Jan 31;34(4):1446-54 - PubMed

References

    1. Cell. 2017 Jul 27;170(3):457-469.e13 - PubMed

References

    1. Cell Signal. 2012 Oct;24(10):1899-908 - PubMed

References

    1. Nature. 2015 Jul 30;523(7562):561-7 - PubMed

References

    1. Sci Rep. 2016 Feb 12;6:21025 - PubMed

References

    1. J Mol Biol. 2010 Jun 11;399(3):501-11 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):810-815 - PubMed

References

    1. J Biol Chem. 2013 Apr 26;288(17):11741-50 - PubMed

References

    1. Biochemistry. 2002 Mar 12;41(10):3321-8 - PubMed

References

    1. Cell. 1999 Apr 16;97(2):257-69 - PubMed

References

    1. J Mol Biol. 2011 Feb 25;406(3):467-78 - PubMed

References

    1. Biochemistry. 1978 Oct 17;17(21):4389-95 - PubMed

References

    1. Handb Exp Pharmacol. 2008;(186):15-37 - PubMed

References

    1. J Mol Biol. 2007 Apr 27;368(2):375-87 - PubMed

References

    1. J Biol Chem. 1997 Jul 18;272(29):18125-31 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449-54 - PubMed

References

    1. J Biol Chem. 2002 Aug 23;277(34):30760-8 - PubMed

References

    1. Biochemistry. 2011 May 10;50(18):3749-63 - PubMed

References

    1. J Biol Chem. 2016 Dec 30;291(53):27147-27159 - PubMed

References

    1. Nature. 1998 Feb 26;391(6670):918-21 - PubMed

References

    1. J Biol Chem. 2011 Aug 12;286(32):27894-901 - PubMed

References

    1. Mol Cell Endocrinol. 1992 Apr;84(3):R39-43 - PubMed

References

    1. J Biol Chem. 2014 Jul 25;289(30):20991-1002 - PubMed

References

    1. J Biol Chem. 2001 Jul 27;276(30):27770-7 - PubMed

References

    1. Sci Rep. 2016 Jun 28;6:28686 - PubMed

References

    1. Biochemistry. 2008 Jan 22;47(3):1070-5 - PubMed

References

    1. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4900-5 - PubMed

References

    1. J Biol Chem. 2009 Jan 2;284(1):685-95 - PubMed

References

    1. J Biol Chem. 2011 Jan 14;286(2):1420-8 - PubMed

References

    1. Neuron. 2005 May 19;46(4):555-67 - PubMed

References

    1. Nat Chem Biol. 2018 Sep;14(9):876-886 - PubMed

References

    1. J Biol Chem. 1995 Mar 17;270(11):6010-6 - PubMed

References

    1. Nat Commun. 2018 Jan 23;9(1):341 - PubMed

References

    1. J Biol Chem. 2000 Dec 29;275(52):41049-57 - PubMed

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