Arrestin-Dependent ERK Activation and Its Disruption

  • Louis M. LuttrellEmail author
  • Benjamin W. Spiller


Regulation of the ERK1/2 cascade is one of the most studied functions of arrestins and illustrates many of the features that enable them to function as GPCR-regulated scaffolds. While all four arrestins can bind the component kinases of the ERK cascade; c-Raf1, MEK1/2 and ERK1/2, their binding is dependent on arrestin conformation, such that inactive ERK1/2 can be sequestered by a microtubule-bound pool of arrestin, while activated ERK1/2 binds with high affinity only to the GPCR-bound arrestin conformation. The result is both a dampening of basal pathway activity, and the arrestin-dependent activation of a spatially and temporally constrained pool of ERK1/2 that differs in function from ERK1/2 activated by G protein-dependent mechanisms or classical receptor tyrosine kinase growth factor receptors. Arrestin-bound ERK1/2 performs numerous functions in cells, among them contributing to the regulation of GPCR internalization and trafficking, control of cell proliferation and non-proliferative cell growth, and regulation of cytoskeletal dynamics involved in cell migration and chemotaxis. The finding that arrestin binding of c-Raf1 and MEK1/2 can be disrupted by point mutations that eliminate its ability to activate ERK1/2 without disrupting its other functions indicates that the two major functions of arrestins, GPCR desensitization and signaling, are dissociable, and offers tools to probe arrestin’s diverse cellular functions.


Arrestin Extracellular signal-regulated kinase G protein-coupled receptor Mitogen-activated protein kinase Signal transduction 



Supported by National Institutes of Health Grants R01 DK055524 (LML), R01 GM095497 (LML), Department of Veterans Affairs Merit Review Grant I01 BX003188 (LML), and the Research Service of the Charleston, SC Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.


  1. Ahn S, Maudsley S, Luttrell LM, Lefkowitz RJ, Daaka Y (1999) Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signaling. J Biol Chem 274:1185–1188CrossRefPubMedGoogle Scholar
  2. Ahn S, Kim J, Lucaveche CL, Reedy MC, Luttrell LM, Lefkowitz RJ, Daaka Y (2002) Src-dependent tyrosine phosphorylation regulates dynamin self-assembly and ligand-induced endocytosis of the epidermal growth factor receptor. J Biol Chem 277:26642–26651CrossRefPubMedGoogle Scholar
  3. Ahn S, Shenoy SK, Wei H, Lefkowitz RJ (2004) Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem 279:35518–35525CrossRefPubMedGoogle Scholar
  4. Anthony DF, Sin YY, Vadrevu S, Advant N, Day JP, Byrne AM, Lynch MJ, Milligan G, Houslay MD, Baillie GS (2011) Beta-arrestin 1 inhibits the GTPase-activating protein function of ARHGAP21, promoting activation of RhoA following angiotensin II type 1A receptor stimulation. Mol Cell Biol 31:1066–1075CrossRefPubMedGoogle Scholar
  5. Aplin M, Christensen GL, Schneider M, Heydorn A, Gammeltoft S, Kjølbye AL, Sheikh SP, Hansen JL (2007) Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes. Basic Clin Pharmacol Toxicol 100:296–301CrossRefPubMedGoogle Scholar
  6. Aragay AM, Mellado M, Frade JM, Martin AM, Jimenez-Sainz MC, Martinez AC, Mayor F Jr (1998) Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2. Proc Natl Acad Sci U S A 95:2985–2990CrossRefPubMedPubMedCentralGoogle Scholar
  7. Aubry L, Guetta D, Klein G (2009) The arrestin fold: variations on a theme. Curr Genomics 10:133–142CrossRefPubMedPubMedCentralGoogle Scholar
  8. Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, Lefkowitz RJ (2005) Beta-arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem 280:8041–8050CrossRefPubMedGoogle Scholar
  9. Bhandari D, Trejo J, Benovic JL, Marchese A (2007) Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4. J Biol Chem 282:36971–36979CrossRefPubMedGoogle Scholar
  10. Bhattacharya M, Anborgh PH, Babwah AV, Dale LB, Dobransky T, Benovic JL, Feldman RD, Verdi JM, Rylett RJ, Ferguson SS (2002) Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nat Cell Biol 4:547–555PubMedGoogle Scholar
  11. Breitman M, Kook S, Gimenez LE, Lizama BN, Palazzo MC, Gurevich EV, Gurevich VV (2012) Silent scaffolds: inhibition of c-Jun N-terminal kinase 3 activity in cell by dominant-negative arrestin-3 mutant. J Biol Chem 287:19653–19664CrossRefPubMedPubMedCentralGoogle Scholar
  12. Burack WR, Shaw AS (2000) Signal transduction: hanging on a scaffold. Curr Opin Cell Biol 12:211–216CrossRefPubMedGoogle Scholar
  13. Carpenter G (2000) EGF receptor transactivation mediated by the proteolytic production of EGF-like agonists. Sci STKE 15:1peGoogle Scholar
  14. Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV (2011a) The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation. PLoS ONE 6:e28723CrossRefPubMedPubMedCentralGoogle Scholar
  15. Coffa S, Breitman M, Spiller BW et al (2011b) A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding. Biochemistry 50:6951–6958CrossRefPubMedPubMedCentralGoogle Scholar
  16. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252CrossRefPubMedGoogle Scholar
  17. DeFea KA (2013) Arrestins in actin reorganization and cell migration. Prog Mol Biol Transl Sci 118:205–222CrossRefPubMedGoogle Scholar
  18. DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW (2000) Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148:1267–1281CrossRefPubMedPubMedCentralGoogle Scholar
  19. DeRooij J, Zwartkruis FL, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL (1998) Epac is a Rap1 guanine nucleotide exchange factor directly activated by cAMP. Nature 396:474–477CrossRefGoogle Scholar
  20. DeWire SM, Kim J, Whalen EJ, Ahn S, Chen M, Lefkowitz RJ (2008) Beta-arrestin-mediated signaling regulates protein synthesis. J Biol Chem 283:10611–10620CrossRefPubMedPubMedCentralGoogle Scholar
  21. Fessart D, Simaan M, Laporte SA (2005) c-Src regulates clathrin adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1 receptor during clathrin-mediated internalization. Mol Endocrinol 19:491–503CrossRefPubMedGoogle Scholar
  22. Fessart D, Simaan M, Zimmerman B, Comeau J, Hamdan FF, Wiseman PW, Bouvier M, Laporte SA (2007) Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex. J Cell Sci 120:1723–1732CrossRefPubMedGoogle Scholar
  23. Galet C, Ascoli M (2008) Arrestin-3 is essential for the activation of Fyn by the luteinizing hormone receptor (LHR) in MA-10 cells. Cell Signal 20:1822–2829CrossRefPubMedPubMedCentralGoogle Scholar
  24. Ge L, Ly Y, Hollenberg M, DeFea K (2003) A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis. J Biol Chem 278:34418–34426CrossRefPubMedGoogle Scholar
  25. Ge L, Shenoy SK, Lefkowitz RJ, DeFea K (2004) Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2. J Biol Chem 279:55419–55424CrossRefPubMedGoogle Scholar
  26. Gesty-Palmer D, El Shewy H, Kohout TA, Luttrell LM (2005) Beta-arrestin 2 expression determines the transcriptional response to lysophosphatidic acid stimulation in murine embryo fibroblasts. J Biol Chem 280:32157–32167CrossRefPubMedGoogle Scholar
  27. Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ (2006) Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem 281:10856–10864CrossRefPubMedGoogle Scholar
  28. Gesty-Palmer D, Yuan L, Martin B, Wood WH 3rd, Lee MH, Janech MG, Tsoi LC, Zheng WJ, Luttrell LM, Maudsley S (2013) β-Arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo. Mol Endocrinol 27:296–314CrossRefPubMedPubMedCentralGoogle Scholar
  29. Godin CM, Ferreira LT, Dale LB, Gros R, Cregan SP, Ferguson SS (2010) The small GTPase Ral couples the angiotensin II type 1 receptor to the activation of phospholipase C-delta 1. Mol Pharmacol 77:388–395CrossRefPubMedGoogle Scholar
  30. Goodman OB Jr, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL (1996) Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature 383:447–450CrossRefPubMedGoogle Scholar
  31. Gurevich VV, Benovic JL (1997) Mechanism of phosphorylation-recognition by visual arrestin and the transition of arrestin into a high affinity binding state. Mol Pharmacol 51:161–169PubMedGoogle Scholar
  32. Gurevich VV, Gurevich EV (2006) The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol Ther 110:465–502CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gurevich VV, Gurevich EV (2013) Structural determinants of arrestin functions. Prog Mol Biol Transl Sci 118:57–92CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hanson SM, Cleghorn WM, Francis DJ, Vishnivetskiy SA, Raman D, Song X, Nair KS, Slepak VZ, Klug CS, Gurevich VV (2007) Arrestin mobilizes signaling proteins to the cytoskeleton and redirects their activity. J Mol Biol 368:375–387CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hanson SM, Vishnivetskiy SA, Hubbell WL, Gurevich VV (2008) Opposing effects of inositol hexakisphosphate on rod arrestin and arrestin2 self-association. Biochemistry 47:1070–1075CrossRefPubMedGoogle Scholar
  36. Hawes BE, van Biesen T, Koch WJ, Luttrell LM, Lefkowitz RJ (1995) Distinct pathways of Gi- and Gq-mediated mitogen activated protein kinase activation. J Biol Chem 270:17148–17153CrossRefPubMedGoogle Scholar
  37. Hunton DL, Barnes WG, Kim J, Ren XR, Violin JD, Reiter E, Milligan G, Patel DD, Lefkowitz RJ (2005) Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Mol Pharmacol 67:1229–1236CrossRefPubMedGoogle Scholar
  38. Jafri F, El-Shewy HM, Lee M-H, Kelly M, Luttrell DK, Luttrell LM (2006) Constitutive ERK1/2 activation by a chimeric neurokinin 1 receptor-beta-arrestin1 fusion protein. Probing the composition and function of the G protein-coupled receptor “signalsome”. J Biol Chem 281:19346–19357CrossRefPubMedGoogle Scholar
  39. Kendall RT, Lee MH, Pleasant DL, Robinson K, Kuppuswamy D, McDermott PJ, Luttrell LM (2014) Arrestin-dependent angiotensin AT1 receptor signaling regulates Akt and mTor-mediated protein synthesis. J Biol Chem 289:26155–26166CrossRefPubMedPubMedCentralGoogle Scholar
  40. Khoury E, Nikolajev L, Simaan M, Namkung Y, Laporte SA (2014) Differential regulation of endosomal GPCR/β-arrestin complexes and trafficking by MAPK. J Biol Chem 289:23302–23317CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kim J, Zhang L, Peppel K, Wu JH, Zidar DA, Brian L, DeWire SM, Exum ST, Lefkowitz RJ, Freedman NJ (2008) Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ Res 103:70–79Google Scholar
  42. Kim J, Ahn S, Rajagopal K, Lefkowitz RJ (2009) Independent beta-arrestin2 and Gq/protein kinase Czeta pathways for ERK stimulated by angiotensin type 1A receptors in vascular smooth muscle cells converge on transactivation of the epidermal growth factor receptor. J Biol Chem 284:11953–11962CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kohout TA, Lin FS, Perry SJ, Conner DA, Lefkowitz RJ (2001) Beta-arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc Natl Acad Sci U S A 98:1601–1606PubMedPubMedCentralGoogle Scholar
  44. Kolch W, Heldecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marmé D, Rapp UR (1993) Protein kinase C alpha activates Raf-1 by direct phosphorylation. Nature 364:249–255CrossRefPubMedGoogle Scholar
  45. Kook S, Zhan X, Kaoud TS, Dalby KN, Gurevich VV, Gurevich EV (2013) Arrestin-3 binds c-Jun N-terminal kinase 1 (JNK1) and JNK2 and facilitates the activation of these ubiquitous JNK isoforms in cells via scaffolding. J Biol Chem 288:37332–37342CrossRefPubMedPubMedCentralGoogle Scholar
  46. Kovoor A, Celver J, Abdryashitov RI, Chavkin C, Gurevich VV (1999) Targeted construction of phosphorylation-independent beta-arrestin mutants with constitutive activity in cells. J Biol Chem 274:6831–6834CrossRefPubMedGoogle Scholar
  47. Kyriakis JM, Avruch J (2012) Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev 92:689–737CrossRefPubMedGoogle Scholar
  48. Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SS, Caron MG, Barak LS (1999) The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci U S A 96:3712–3717CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lee MH, El-Shewy HM, Luttrell DK, Luttrell LM (2008) Role of beta-arrestin-mediated desensitization and signaling in the control of angiotensin AT1a receptor-stimulated transcription. J Biol Chem 283:2088–2097CrossRefPubMedGoogle Scholar
  50. Lefkowitz RJ, Pierce KL, Luttrell LM (2002) Dancing with different partners: PKA phosphorylation of seven membrane-spanning receptors regulates their G protein coupling specificity. Mol Pharmacol 62:971–974CrossRefPubMedGoogle Scholar
  51. Li TT, Alemayehu M, Aziziyeh AI, Pape C, Pampillo M, Postovit LM, Mills GB, Babwah AV, Bhattacharya M (2009a) Beta-arrestin/Ral signaling regulates lysophosphatidic acid-mediated migration and invasion of human breast tumor cells. Mol Cancer Res 7:1064–1077CrossRefPubMedGoogle Scholar
  52. Li X, MacLeod R, Dunlop AJ, Edwards HV, Advant N, Gibson LC, Devine NM, Brown KM, Adams DR, Houslay MD, Baillie GS (2009b) A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex. FEBS Lett 583:3310–3316CrossRefPubMedGoogle Scholar
  53. Lin FT, Krueger KM, Kendall HE, Daaka Y, Fredericks ZL, Pitcher JA, Lefkowitz RJ (1997) Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1. J Biol Chem 272:31051–31057CrossRefPubMedGoogle Scholar
  54. Lin FT, Miller WE, Luttrell LM, Lefkowitz RJ (1999) Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases. J Biol Chem 274:15971–15974CrossRefPubMedGoogle Scholar
  55. Luttrell LM (2003) Location, location, location. Spatial and temporal regulation of MAP kinases by G protein-coupled receptors. J Mol Endocrinol 30:117–126CrossRefPubMedGoogle Scholar
  56. Luttrell LM, Gesty-Palmer D (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 62:305–330CrossRefPubMedPubMedCentralGoogle Scholar
  57. Luttrell LM, Miller WE (2013) Arrestins as regulators of kinases and phosphatases. Prog Mol Biol Transl Sci 118:115–147CrossRefPubMedGoogle Scholar
  58. Luttrell LM, Hawes BE, van Biesen T, Luttrell DK, Lansing TJ, Lefkowitz RJ (1996) Role of c-Src in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen activated protein kinases. J Biol Chem 271:19443–19450CrossRefPubMedGoogle Scholar
  59. Luttrell LM, Della Rocca GJ, van Biesen T, Luttrell DK, Lefkowitz RJ (1997) Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. J Biol Chem 272:4637–4644CrossRefPubMedGoogle Scholar
  60. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661CrossRefPubMedGoogle Scholar
  61. Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A 98:2449–2454CrossRefPubMedPubMedCentralGoogle Scholar
  62. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577CrossRefPubMedGoogle Scholar
  63. McLaughlin NJ, Banerjee A, Kelher MR, Gamboni-Robertson F, Hamiel C, Sheppard FR, Moore EE, Silliman CC (2006) Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol 176:7039–7050CrossRefPubMedGoogle Scholar
  64. Meng D, Lynch MJ, Huston E, Beyermann M, Eichhorst J, Adams DR, Klusmann E, Houslay MD, Baillie GS (2009) MEK1 binds directly to beta-arrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization. J Biol Chem 284:11425–11435Google Scholar
  65. Miura S, Zhang J, Matsuo Y, Saku K, Karnik SS (2004) Activation of extracellular signal-activated kinase by angiotensin II-induced Gq-independent epidermal growth factor receptor transactivation. Hypertens Res 27:65–77Google Scholar
  66. Nelson CD, Perry SJ, Regier DS, Prescott SM, Topham MK, Lefkowitz RJ (2007) Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins. Science 315:663–666CrossRefPubMedGoogle Scholar
  67. Noma T, Lemaire A, Prasad SVN, Barki-Harrington L, Tilley DG, Chen J, Le Corvoisier P, Violin JD, Wei H, Lefkowitz RJ, Rockman HA (2007) Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest 117:2445–2458CrossRefPubMedPubMedCentralGoogle Scholar
  68. Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS (2000) Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 275:17201–17210CrossRefPubMedGoogle Scholar
  69. Oakley RH, Laporte SA, Holt JA, Barak LS, Caron MG (2001) Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis. J Biol Chem 276:19452–19460CrossRefPubMedGoogle Scholar
  70. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183PubMedGoogle Scholar
  71. Penela P, Elorza A, Sarnago S, Mayor F Jr (2001) Beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. EMBO J 20:5129–5138Google Scholar
  72. Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, Miller WE, McLean AJ, Conti M, Houslay MD, Lefkowitz RJ (2002) Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science 298:834–836CrossRefPubMedGoogle Scholar
  73. Scott MG, Le Rouzic E, Perianin A, Pierotti V, Enslen H, Benichou S, Marullo S, Benmerah A (2002) Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2. J Biol Chem 277:37693–37701CrossRefPubMedGoogle Scholar
  74. Scott MG, Pierotti V, Storez H, Lindberg E, Thuret A, Muntaner O, Labbé-Jullié C, Pitcher JA, Marullo S (2006) Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins. Mol Cell Biol 26:3432–3445CrossRefPubMedPubMedCentralGoogle Scholar
  75. Seo J, Tsakem EL, Breitman M, Gurevich VV (2011) Identification of arrestin-3-specific residues necessary for JNK3 kinase activation. J Biol Chem 286:27894–27901CrossRefPubMedPubMedCentralGoogle Scholar
  76. Shenoy SK, Lefkowitz RJ (2003) Trafficking pattern of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination. J Biol Chem 278:14498–14506CrossRefPubMedGoogle Scholar
  77. Shenoy SK, Lefkowitz RJ (2005) Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. J Biol Chem 280:15315–15324CrossRefPubMedGoogle Scholar
  78. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ (2006) Beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 281:1261–1273CrossRefPubMedGoogle Scholar
  79. Shenoy SK, Xiao K, Venkataramanan V, Snyder PM, Freedman NJ, Weissman AM (2008) Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor. J Biol Chem 283:22166–22176CrossRefPubMedPubMedCentralGoogle Scholar
  80. Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ (2009) Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A 106:6650–6655CrossRefPubMedPubMedCentralGoogle Scholar
  81. Song X, Raman D, Gurevich EV, Vishnivetskiy SA, Gurevich VV (2006) Visual and both non-visual arrestins in their “inactive” conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem 281:21491–21499CrossRefPubMedPubMedCentralGoogle Scholar
  82. Song X, Coffa S, Fu H, Gurevich VV (2009) How does arrestin assemble MAPKs into a signaling complex? J Biol Chem 284:685–695CrossRefPubMedPubMedCentralGoogle Scholar
  83. Stork PJ (2002) ERK signaling: duration, duration, duration. Cell Cycle 1:315–317CrossRefPubMedGoogle Scholar
  84. Sun Y, Cheng Z, Ma L, Pei G (2002) Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J Biol Chem 277:49212–49219CrossRefPubMedGoogle Scholar
  85. Tohgo A, Pierce KL, Choy EW, Lefkowitz RJ, Luttrell LM (2002) βarrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK mediated transcription following angiotensin AT1a receptor stimulation. J Biol Chem 277:9429–9436CrossRefPubMedGoogle Scholar
  86. Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, Caron MG, Lefkowitz RJ, Luttrell LM (2003) The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem 278:6258–6267CrossRefPubMedGoogle Scholar
  87. Tomhave ED, Richardson RM, Didsbury JR, Menard L, Snyderman R, Ali H (1994) Cross-desensitization of receptors for peptide chemoattractants. Characterization of a new form of leukocyte regulation. J Immunol 153:3267–3275PubMedGoogle Scholar
  88. van Biesen T, Hawes BE, Luttrell DK, Krueger KM, Touhara K, Porfiri E, Sakaue M, Luttrell LM, Lefkowitz RJ (1995) Receptor-tyrosine-kinase- and Gbetagamma-mediated MAP kinase activation by a common signalling pathway. Nature 376:781–784CrossRefPubMedGoogle Scholar
  89. Vishnivetskiy SA, Hirsch JA, Velez MG, Gurevich YV, Gurevich VV (2002) Transition of arrestin into the active receptor-binding state requires an extended interdomain hinge. J Biol Chem 277:43961–43967CrossRefPubMedGoogle Scholar
  90. Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap-1-dependent pathway. Cell 89:73–82CrossRefPubMedGoogle Scholar
  91. Wei H, Ahn S, Shenoy SK, Karnik SS, Hunyady L, Luttrell LM, Lefkowitz RJ (2003) Independent G protein and beta-arrestin2 mediated activation of ERK by angiotensin. Proc Natl Acad Sci U S A 100:10782–10787CrossRefPubMedPubMedCentralGoogle Scholar
  92. Wei H, Ahn S, Barnes WG, Lefkowitz RJ (2004) Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2. J Biol Chem 279:48255–48261CrossRefPubMedGoogle Scholar
  93. White MF (1998) The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 182:3–11CrossRefPubMedGoogle Scholar
  94. Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW (1993) Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3′,5′-monophosphate. Science 62:1065–1068CrossRefGoogle Scholar
  95. Xu TR, Baillie GS, Bhari N, Houslay TM, Pitt AM, Adams DR, Kolch W, Houslay MD, Milligan G (2008) Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta2-adrenoceptor and the ERK1/2 MAPKs: implications for beta2-adrenoceptor signalling via the ERK1/2 MAPKs. Biochem J 413:51–60CrossRefPubMedGoogle Scholar
  96. Zhan X, Kaoud TS, Dalby KN, Gurevich VV (2011) Nonvisual arrestins function as simple scaffolds assembling the MKK4–JNK3α2 signaling complex. Biochemistry 50:10520–10529CrossRefPubMedPubMedCentralGoogle Scholar
  97. Zimmerman B, Simaan M, Lee M-H, Luttrell LM, Laporte SA (2009) c-Src-mediated phosphorylation of AP-2 reveals a general mechanism for receptors internalizing through the clathrin pathway. Cell Signal 21:103–110CrossRefPubMedGoogle Scholar
  98. Zoudilova M, Kumar P, Ge L, Wang P, Bokoch GM, DeFea KA (2007) Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J Biol Chem 282:20634–20646CrossRefPubMedGoogle Scholar
  99. Zoudilova M, Min J, Richards HL, Carter D, Huang T, DeFea KA (2010) Beta-arrestins scaffold cofilin with chronophin to direct localized actin filament severing and membrane protrusions downstream of protease-activated receptor-2. J Biol Chem 285:14318–14329CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of MedicineMedical University of South CarolinaCharlestonUSA
  2. 2.Ralph H. Johnson Veterans Affairs Medical CenterCharlestonUSA
  3. 3.Department of Microbiology and ImmunologyVanderbilt UniversityNashvilleUSA
  4. 4.Division of Endocrinology, Diabetes and Medical GeneticsMedical University of South CarolinaCharlestonUSA

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