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PMID: 18037927 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Beta-arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction.

British journal of pharmacology ·Vol. 153 Suppl 1 ·2008-03-00 ·Pages S298-309

Defea K

Abstract

G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7-TMRs), are the largest protein receptor superfamily in the body. These receptors and their ligands direct a diverse array of physiological responses, and hence have broad relevance to numerous diseases. As a result, they have generated considerable interest in the pharmaceutical industry as drug targets. Recently, GPCRs have been demonstrated to elicit signals through interaction with the scaffolding proteins, beta-arrestins-1 and 2, independent of heterotrimeric G-protein coupling. This review discusses several known G-protein-independent, beta-arrestin-dependent pathways and their potential physiological and pharmacological significance. The emergence of G-protein-independent signalling changes the way in which GPCR signalling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics.

MeSH Terms
Actin Depolymerizing Factors/physiology Animals Arrestins/chemistry,physiology Enzyme Activation/physiology GTP-Binding Proteins/chemistry,physiology Humans Mitogen-Activated Protein Kinases/metabolism NF-kappa B/physiology Phosphatidylinositol 3-Kinases/physiology Signal Transduction/physiology beta-Arrestins
Chemicals
Actin Depolymerizing Factors Arrestins NF-kappa B beta-Arrestins Phosphatidylinositol 3-Kinases Mitogen-Activated Protein Kinases GTP-Binding Proteins
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Defea K
Biomedical Sciences Division, University of California, Riverside, 1620 Computer Statistics Bldg, Riverside, CA 92521, USA. [email protected]
References (90)
90 references, click to expand
  1. Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2.
    J Biol Chem. 2007 Jul 13;282(28):20634-46 PMID: 17500066
  2. The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex.
    Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11086-91 PMID: 10995467
  3. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases.
    Nephrol Dial Transplant. 2006 Jan;21(1):16-20 PMID: 16280370
  4. Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis.
    Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13936-41 PMID: 11717450
  5. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial.
    JAMA. 2004 Apr 28;291(16):1963-71 PMID: 15113814
  6. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1448-53 PMID: 15671180
  7. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
    Science. 1999 Jan 29;283(5402):655-61 PMID: 9924018
  8. Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7.
    J Biol Chem. 2004 May 28;279(22):23214-22 PMID: 15054093
  9. Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells.
    Cancer Res. 2006 Jan 1;66(1):307-14 PMID: 16397244
  10. Transient exposure to PTHrP (107-139) exerts anabolic effects through vascular endothelial growth factor receptor 2 in human osteoblastic cells in vitro.
    Calcif Tissue Int. 2006 Nov;79(5):360-9 PMID: 17120184
  11. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.
    J Biol Chem. 2006 Jan 13;281(2):1261-73 PMID: 16280323
  12. Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking.
    Mol Pharmacol. 2005 Jan;67(1):78-87 PMID: 15475570
  13. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.
    Science. 2000 Nov 24;290(5496):1574-7 PMID: 11090355
  14. Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation.
    J Biol Chem. 2003 Nov 21;278(47):46814-25 PMID: 12954641
  15. Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta opioid receptor heterodimers.
    FASEB J. 2007 Aug;21(10):2455-65 PMID: 17384143
  16. G protein-independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cells.
    J Physiol. 2007 Jun 1;581(Pt 2):693-708 PMID: 17379632
  17. Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR.
    EMBO J. 2007 Jan 10;26(1):53-64 PMID: 17170700
  18. Differential effects of beta-arrestins on the internalization, desensitization and ERK1/2 activation downstream of protease activated receptor-2.
    Am J Physiol Cell Physiol. 2007 Jul;293(1):C346-57 PMID: 17442737
  19. Functional specialization of beta-arrestin interactions revealed by proteomic analysis.
    Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12011-6 PMID: 17620599
  20. beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking.
    Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1601-6 PMID: 11171997
  21. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10782-7 PMID: 12949261
  22. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells.
    Cancer Res. 2001 Aug 1;61(15):5933-40 PMID: 11479236
  23. Protease-activated receptors: how proteases signal to cells.
    Curr Opin Pharmacol. 2001 Dec;1(6):575-82 PMID: 11757812
  24. Palmitoylation of the V2 vasopressin receptor carboxyl tail enhances beta-arrestin recruitment leading to efficient receptor endocytosis and ERK1/2 activation.
    J Biol Chem. 2003 Oct 17;278(42):41541-51 PMID: 12900404
  25. Arrestin-mediated ERK activation by gonadotropin-releasing hormone receptors: receptor-specific activation mechanisms and compartmentalization.
    J Biol Chem. 2006 Feb 3;281(5):2701-10 PMID: 16314413
  26. Stop that cell! Beta-arrestin-dependent chemotaxis: a tale of localized actin assembly and receptor desensitization.
    Annu Rev Physiol. 2007;69:535-60 PMID: 17002593
  27. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
    J Cell Biol. 2000 Mar 20;148(6):1267-81 PMID: 10725339
  28. AT1 receptor blocker-insensitive mutant AT1A angiotensin receptors reveal the presence of G protein-independent signaling in C9 cells.
    Biochem Pharmacol. 2007 May 15;73(10):1582-92 PMID: 17284329
  29. Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: in vivo analyses in rodent models of arthritis and ex vivo analyses in human inflammatory synovitis.
    Arthritis Rheum. 2007 Feb;56(2):441-7 PMID: 17265479
  30. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1.
    J Biol Chem. 2005 Jul 1;280(26):25048-59 PMID: 15878870
  31. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11406-11 PMID: 13679574
  32. Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor.
    J Biol Chem. 2004 Aug 20;279(34):35518-25 PMID: 15205453
  33. Stimulation by ghrelin of p42/p44 mitogen-activated protein kinase through the GHS-R1a receptor: role of G-proteins and beta-arrestins.
    J Cell Physiol. 2007 Oct;213(1):187-200 PMID: 17525997
  34. Beta-arrestin-biased ligands at seven-transmembrane receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):416-22 PMID: 17644195
  35. Vasopressin-induced vasoconstriction is dependent on MAPKerk1/2 phosphorylation.
    Fundam Clin Pharmacol. 2004 Feb;18(1):45-50 PMID: 14748753
  36. Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis.
    Mol Pharmacol. 2005 Apr;67(4):1229-36 PMID: 15635042
  37. Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase.
    J Biol Chem. 1998 Jan 9;273(2):685-8 PMID: 9422717
  38. Protease-activated receptor-2 simultaneously directs beta-arrestin-1-dependent inhibition and Galphaq-dependent activation of phosphatidylinositol 3-kinase.
    Biochemistry. 2006 Aug 8;45(31):9374-85 PMID: 16878972
  39. Role of endocytosis in the activation of the extracellular signal-regulated kinase cascade by sequestering and nonsequestering G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1489-94 PMID: 10677489
  40. Distinct roles for Src tyrosine kinase in beta2-adrenergic receptor signaling to MAPK and in receptor internalization.
    J Biol Chem. 2004 May 14;279(20):21637-42 PMID: 14990578
  41. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.
    Cell. 2005 Jul 29;122(2):261-73 PMID: 16051150
  42. Unconventional homologous internalization of the angiotensin II type-1 receptor induced by G-protein-independent signals.
    Hypertension. 2005 Aug;46(2):419-25 PMID: 15998700
  43. Role of G protein-coupled receptor kinase 4 and beta-arrestin 1 in agonist-stimulated metabotropic glutamate receptor 1 internalization and activation of mitogen-activated protein kinases.
    J Biol Chem. 2003 Apr 4;278(14):12433-42 PMID: 12519791
  44. A protective role for protease-activated receptors in the airways.
    Nature. 1999 Mar 11;398(6723):156-60 PMID: 10086357
  45. Hyperactive vasopressin receptors and disturbed water homeostasis.
    N Engl J Med. 2005 May 5;352(18):1847-50 PMID: 15872199
  46. Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases.
    J Biol Chem. 1999 Jun 4;274(23):15971-4 PMID: 10347142
  47. Signal switching, crosstalk, and arrestin scaffolds: novel G protein-coupled receptor signaling in cardiovascular disease.
    Hypertension. 2006 Aug;48(2):173-9 PMID: 16818801
  48. The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling.
    Cell Signal. 2007 Jan;19(1):32-41 PMID: 16857342
  49. Angiotensin receptor blockers in hypertension and cardiovascular diseases.
    Cardiovasc Hematol Agents Med Chem. 2006 Jan;4(1):67-73 PMID: 16529551
  50. Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A.
    Nature. 1997 Nov 6;390(6655):88-91 PMID: 9363896
  51. Bone response to intermittent parathyroid hormone is altered in mice null for {beta}-Arrestin2.
    Endocrinology. 2005 Apr;146(4):1854-62 PMID: 15705780
  52. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.
    Am J Pathol. 2002 Nov;161(5):1903-15 PMID: 12414536
  53. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.
    J Biol Chem. 2003 Feb 21;278(8):6258-67 PMID: 12473660
  54. Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1442-7 PMID: 15671181
  55. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.
    Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16284-9 PMID: 17060617
  56. Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110 alpha and beta by protease-activated receptor 2 and beta-arrestins.
    Biochem J. 2007 Dec 1;408(2):221-30 PMID: 17680774
  57. Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons.
    J Biol Chem. 2006 Nov 10;281(45):34515-24 PMID: 16982618
  58. Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling.
    Biochem J. 2003 Nov 1;375(Pt 3):503-15 PMID: 12959637
  59. Receptor activity-independent recruitment of betaarrestin2 reveals specific signalling modes.
    EMBO J. 2004 Oct 13;23(20):3950-61 PMID: 15385966
  60. beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation.
    J Biol Chem. 2005 Mar 4;280(9):8041-50 PMID: 15611106
  61. Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages.
    J Biol Chem. 2006 Nov 10;281(45):34159-70 PMID: 16980301
  62. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
    J Cell Sci. 2002 Feb 1;115(Pt 3):455-65 PMID: 11861753
  63. Beta-arrestin-dependent parathyroid hormone-stimulated extracellular signal-regulated kinase activation and parathyroid hormone type 1 receptor internalization.
    Endocrinology. 2007 Aug;148(8):4073-9 PMID: 17525124
  64. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.
    J Biol Chem. 2006 Apr 21;281(16):10856-64 PMID: 16492667
  65. Thrombin receptors activate G(o) proteins in endothelial cells to regulate intracellular calcium and cell shape changes.
    J Biol Chem. 2002 Sep 13;277(37):34143-9 PMID: 12039967
  66. Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice.
    J Clin Invest. 2005 Nov;115(11):3045-56 PMID: 16276415
  67. Identification of structural determinants for G protein-independent activation of mitogen-activated protein kinases in the seventh transmembrane domain of the angiotensin II type 1 receptor.
    Mol Endocrinol. 2006 Aug;20(8):1924-34 PMID: 16556732
  68. G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.
    Adv Second Messenger Phosphoprotein Res. 1997;31:263-77 PMID: 9344257
  69. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2.
    J Biol Chem. 2004 Dec 31;279(53):55419-24 PMID: 15489220
  70. beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.
    J Biol Chem. 2002 Mar 15;277(11):9429-36 PMID: 11777902
  71. Protease-activated receptor-2 (PAR2) in the airways.
    Pulm Pharmacol Ther. 2001;14(3):183-91 PMID: 11448145
  72. Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis.
    J Biol Chem. 2003 Dec 19;278(51):51334-9 PMID: 14534298
  73. Signaling at zero G: G-protein-independent functions for 7-TM receptors.
    Trends Biochem Sci. 2001 May;26(5):291-7 PMID: 11343921
  74. Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation.
    J Biol Chem. 2002 Dec 20;277(51):49212-9 PMID: 12370187
  75. Beta-arrestin2 enhances beta2-adrenergic receptor-mediated nuclear translocation of ERK.
    Cell Signal. 2005 Oct;17(10):1248-53 PMID: 16038799
  76. The Akt-GSK-3 signaling cascade in the actions of dopamine.
    Trends Pharmacol Sci. 2007 Apr;28(4):166-72 PMID: 17349698
  77. Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism.
    Diabetes. 2007 Mar;56(3):641-6 PMID: 17327431
  78. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449-54 PMID: 11226259
  79. Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways.
    J Allergy Clin Immunol. 2005 Mar;115(3):623-30 PMID: 15753914
  80. Beta-adrenergic stimulation induces interleukin-18 expression via beta2-AR, PI3K, Akt, IKK, and NF-kappaB.
    Biochem Biophys Res Commun. 2004 Jun 25;319(2):304-11 PMID: 15178407
  81. Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2.
    Vasc Med. 2007 Feb;12(1):23-7 PMID: 17451090
  82. Endogenous regulator of G protein signaling proteins suppress Galphao-dependent, mu-opioid agonist-mediated adenylyl cyclase supersensitization.
    J Pharmacol Exp Ther. 2004 Jul;310(1):215-22 PMID: 15014136
  83. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways.
    Mol Cell. 2004 May 7;14(3):303-17 PMID: 15125834
  84. Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization.
    Nat Cell Biol. 2002 Aug;4(8):547-55 PMID: 12105416
  85. A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis.
    J Biol Chem. 2003 Sep 5;278(36):34418-26 PMID: 12821670
  86. Vascular benefits of angiotensin receptor blockers.
    Expert Opin Investig Drugs. 2007 Jul;16(7):987-97 PMID: 17594184
  87. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.
    J Pharmacol Exp Ther. 1998 Dec;287(3):860-7 PMID: 9864265
  88. Ubiquitination of beta-arrestin links seven-transmembrane receptor endocytosis and ERK activation.
    J Biol Chem. 2007 Oct 5;282(40):29549-62 PMID: 17666399
  89. The angiotensin type 1 receptor activates extracellular signal-regulated kinases 1 and 2 by G protein-dependent and -independent pathways in cardiac myocytes and langendorff-perfused hearts.
    Basic Clin Pharmacol Toxicol. 2007 May;100(5):289-95 PMID: 17448113
  90. Arrestin serves as a molecular switch, linking endogenous alpha2-adrenergic receptor to SRC-dependent, but not SRC-independent, ERK activation.
    J Biol Chem. 2006 Sep 8;281(36):25948-55 PMID: 16809338
Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0707508
Email
[email protected]
Published
2008-03-00
Epub
2007-00-26
Pages
S298-309
Language
English
Region
England
NLM ID
7502536
PMCID
PMC2268080
Subset
IM
Grants
NIGMS NIH HHS · R01 GM066151 · United States
NIGMS NIH HHS · R01 GM066151-04 · United States
NIGMS NIH HHS · R01GM066151 · United States
External Links
PubMed source DOI: 10.1038/sj.bjp.0707508 PMC Full Text View journal details
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