|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 281, Issue 2, 1261-1273, January 13, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-Arrestin-dependent, G Protein-independent ERK1/2 Activation by the 2 Adrenergic Receptor*
12
||¶||3
From the
Howard Hughes Medical Institute at Duke University Medical Center, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, the ¶Institut National De La Recherche Agronomique, 37380 Nouzilly, France, Program in Structural and Computational Biology and Molecular Biophysics and the ||Molecular and Human Genetics Department, Baylor College of Medicine, Houston, Texas 77030
Physiological effects of 
adrenergic receptor (2AR) stimulation have been classically shown to result from Gs-dependent adenylyl cyclase activation. Here we demonstrate a novel signaling mechanism wherein -arrestins mediate 2AR signaling to extracellular-signal regulated kinases 1/2 (ERK 1/2) independent of G protein activation. Activation of ERK1/2 by the 2AR expressed in HEK-293 cells was resolved into two components dependent, respectively, on Gs-Gi/protein kinase A (PKA) or -arrestins. G protein-dependent activity was rapid, peaking within 2-5 min, was quite transient, was blocked by pertussis toxin (Gi inhibitor) and H-89 (PKA inhibitor), and was insensitive to depletion of endogenous -arrestins by siRNA. -Arrestin-dependent activation was slower in onset (peak 5-10 min), less robust, but more sustained and showed little decrement over 30 min. It was insensitive to pertussis toxin and H-89 and sensitive to depletion of either -arrestin1 or -2 by small interfering RNA. In Gs knock-out mouse embryonic fibroblasts, wild-type 2AR recruited -arrestin2-green fluorescent protein and activated pertussis toxin-insensitive ERK1/2. Furthermore, a novel 2AR mutant (2ART68F,Y132G,Y219A or 2ARTYY), rationally designed based on Evolutionary Trace analysis, was incapable of G protein activation but could recruit -arrestins, undergo -arrestin-dependent internalization, and activate -arrestin-dependent ERK. Interestingly, overexpression of GRK5 or -6 increased mutant receptor phosphorylation and -arrestin recruitment, led to the formation of stable receptor--arrestin complexes on endosomes, and increased agonist-stimulated phospho-ERK1/2. In contrast, GRK2, membrane translocation of which requires G
release upon G protein activation, was ineffective unless it was constitutively targeted to the plasma membrane by a prenylation signal (CAAX). These findings demonstrate that the 2AR can signal to ERK via a GRK5/6--arrestin-dependent pathway, which is independent of G protein coupling.
Received for publication, June 16, 2005 , and in revised form, November 2, 2005.
* This work was supported in part by National Institutes of Health (NIH) Grants HL16037 and HL70631 (to R. J. L.) and GM66099 (to O. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by American Heart Association Scientist Development Grant 0530014N.
2 Supported by NIH Training Grant T32-DK-00701.
3 An investigator with the Howard Hughes Medical Institute. To whom correspondence should be addressed: Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  D. G. Tilley, I.-M. Kim, P. A. Patel, J. D. Violin, and H. A. Rockman {beta}-Arrestin Mediates {beta}1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream Signaling J. Biol. Chem., July 24, 2009; 284(30): 20375 - 20386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Zidar, J. D. Violin, E. J. Whalen, and R. J. Lefkowitz Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands PNAS, June 16, 2009; 106(24): 9649 - 9654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dominguez, E. Hu, M. Zhou, and M. Baudry 17{beta}-Estradiol-Mediated Neuroprotection and ERK Activation Require a Pertussis Toxin-Sensitive Mechanism Involving GRK2 and {beta}-Arrestin-1 J. Neurosci., April 1, 2009; 29(13): 4228 - 4238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ahn, J. Kim, M. R. Hara, X.-R. Ren, and R. J. Lefkowitz {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation J. Biol. Chem., March 27, 2009; 284(13): 8855 - 8865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cai, J.-H. Wu, S. T. Exum, M. Oppermann, R. T. Premont, S. K. Shenoy, and N. J. Freedman Reciprocal Regulation of the Platelet-Derived Growth Factor Receptor-{beta} and G Protein-Coupled Receptor Kinase 5 by Cross-Phosphorylation: Effects on Catalysis Mol. Pharmacol., March 1, 2009; 75(3): 626 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Scarselli and J. G. Donaldson Constitutive Internalization of G Protein-coupled Receptors and G Proteins via Clathrin-independent Endocytosis J. Biol. Chem., February 6, 2009; 284(6): 3577 - 3585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. McAlees and V. M. Sanders Hematopoietic Protein Tyrosine Phosphatase Mediates {beta}2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes Mol. Cell. Biol., February 1, 2009; 29(3): 675 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y.-H. Woo, T.-B. Wang, X. Zeng, W. Zhu, D. R. Abernethy, I. W. Wainer, and R.-P. Xiao Stereochemistry of an Agonist Determines Coupling Preference of {beta}2-Adrenoceptor to Different G Proteins in Cardiomyocytes Mol. Pharmacol., January 1, 2009; 75(1): 158 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Labasque, E. Reiter, C. Becamel, J. Bockaert, and P. Marin Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling Mol. Biol. Cell, November 1, 2008; 19(11): 4640 - 4650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gong, Z. Li, M. Xu, J. Du, Z. Lv, and Y. Zhang A Novel Protein Kinase A-independent, {beta}-Arrestin-1-dependent Signaling Pathway for p38 Mitogen-activated Protein Kinase Activation by {beta}2-Adrenergic Receptors J. Biol. Chem., October 24, 2008; 283(43): 29028 - 29036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Byers, P. A. Calloway, L. Shannon, H. D. Cunningham, S. Smith, F. Li, B. C. Fassold, and C. M. Vines Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21 J. Immunol., October 1, 2008; 181(7): 4723 - 4732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I.-M. Kim, D. G. Tilley, J. Chen, N. C. Salazar, E. J. Whalen, J. D. Violin, and H. A. Rockman {beta}-Blockers alprenolol and carvedilol stimulate {beta}-arrestin-mediated EGFR transactivation PNAS, September 23, 2008; 105(38): 14555 - 14560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Bruss, W. Richter, K. Horner, S.-L. C. Jin, and M. Conti Critical Role of PDE4D in {beta}2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts J. Biol. Chem., August 15, 2008; 283(33): 22430 - 22442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. V. Gurevich and E. V. Gurevich Rich Tapestry of G Protein-Coupled Receptor Signaling and Regulatory Mechanisms Mol. Pharmacol., August 1, 2008; 74(2): 312 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Shukla, J. D. Violin, E. J. Whalen, D. Gesty-Palmer, S. K. Shenoy, and R. J. Lefkowitz Distinct conformational changes in {beta}-arrestin report biased agonism at seven-transmembrane receptors PNAS, July 22, 2008; 105(29): 9988 - 9993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kim, L. Zhang, K. Peppel, J.-H. Wu, D. A. Zidar, L. Brian, S. M. DeWire, S. T. Exum, R. J. Lefkowitz, and N. J. Freedman {beta}-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration Circ. Res., July 3, 2008; 103(1): 70 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Galandrin, G. Oligny-Longpre, H. Bonin, K. Ogawa, C. Gales, and M. Bouvier Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the {beta}1-Adrenergic Receptor Mol. Pharmacol., July 1, 2008; 74(1): 162 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, and R. J. Lefkowitz {beta}-Arrestin-biased Agonism at the {beta}2-Adrenergic Receptor J. Biol. Chem., February 29, 2008; 283(9): 5669 - 5676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Barki-Harrington and H. A. Rockman {beta}-Arrestins: Multifunctional Cellular Mediators Physiology, February 1, 2008; 23(1): 17 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-H. Lee, H. M. El-Shewy, D. K. Luttrell, and L. M. Luttrell Role of -Arrestin-mediated Desensitization and Signaling in the Control of Angiotensin AT1a Receptor-stimulated Transcription J. Biol. Chem., January 25, 2008; 283(4): 2088 - 2097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zheng, H. H. Loh, and P.-Y. Law -Arrestin-Dependent {micro}-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation Mol. Pharmacol., January 1, 2008; 73(1): 178 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Faucher, F. E. Gannier, J. M. Lignon, P. Cosnay, and C. O. Malecot Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of {beta}2-adrenoceptor agonists in guinea pig right papillary muscles Am J Physiol Cell Physiol, January 1, 2008; 294(1): C106 - C117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Wisler, S. M. DeWire, E. J. Whalen, J. D. Violin, M. T. Drake, S. Ahn, S. K. Shenoy, and R. J. Lefkowitz A unique mechanism of beta-blocker action: Carvedilol stimulates beta-arrestin signaling PNAS, October 16, 2007; 104(42): 16657 - 16662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Shenoy, L. S. Barak, K. Xiao, S. Ahn, M. Berthouze, A. K. Shukla, L. M. Luttrell, and R. J. Lefkowitz Ubiquitination of beta-Arrestin Links Seven-transmembrane Receptor Endocytosis and ERK Activation J. Biol. Chem., October 5, 2007; 282(40): 29549 - 29562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Wayne, H.-Y. Fan, X. Cheng, and J. S. Richards Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation Mol. Endocrinol., August 1, 2007; 21(8): 1940 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Rozenfeld and L. A. Devi Receptor heterodimerization leads to a switch in signaling: {beta}-arrestin2-mediated ERK activation by {micro}-{delta} opioid receptor heterodimers FASEB J, August 1, 2007; 21(10): 2455 - 2465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Jorgensen, V. Kubale, M. Vrecl, T. W. Schwartz, and C. E. Elling Oxyntomodulin Differentially Affects Glucagon-Like Peptide-1 Receptor beta-Arrestin Recruitment and Signaling through G{alpha} J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 148 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Geldner, D. L. Hyman, X. Wang, K. Schumacher, and J. Chory Endosomal signaling of plant steroid receptor kinase BRI1 Genes & Dev., July 1, 2007; 21(13): 1598 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Barthet, B. Framery, F. Gaven, L. Pellissier, E. Reiter, S. Claeysen, J. Bockaert, and A. Dumuis 5-Hydroxytryptamine4 Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Depends on Src Activation but Not on G Protein or beta-Arrestin Signaling Mol. Biol. Cell, June 1, 2007; 18(6): 1979 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Neubig Missing Links: Mechanisms of Protean Agonism Mol. Pharmacol., May 1, 2007; 71(5): 1200 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Grabauskas, B. Lancaster, V. O'Connor, and H. V. Wheal Protein kinase signalling requirements for metabotropic action of kainate receptors in rat CA1 pyramidal neurones J. Physiol., March 1, 2007; 579(2): 363 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Groer, K. Tidgewell, R. A. Moyer, W. W. Harding, R. B. Rothman, T. E. Prisinzano, and L. M. Bohn An Opioid Agonist that Does Not Induce {micro}-Opioid Receptor--Arrestin Interactions or Receptor Internalization Mol. Pharmacol., February 1, 2007; 71(2): 549 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ma and G. Pei beta-arrestin signaling and regulation of transcription J. Cell Sci., January 15, 2007; 120(2): 213 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Breit, K. Wolff, H. Kalwa, H. Jarry, T. Buch, and T. Gudermann The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors J. Biol. Chem., December 8, 2006; 281(49): 37447 - 37456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. El-Yazbi, W. J. Cho, R. Schulz, and E. E. Daniel Caveolin-1 knockout alters beta-adrenoceptors function in mouse small intestine Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G1020 - G1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Macey, J. D. Lowe, and C. Chavkin Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons J. Biol. Chem., November 10, 2006; 281(45): 34515 - 34524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kara, P. Crepieux, C. Gauthier, N. Martinat, V. Piketty, F. Guillou, and E. Reiter A Phosphorylation Cluster of Five Serine and Threonine Residues in the C-Terminus of the Follicle-Stimulating Hormone Receptor Is Important for Desensitization But Not for ss-Arrestin-Mediated ERK Activation Mol. Endocrinol., November 1, 2006; 20(11): 3014 - 3026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rajagopal, E. J. Whalen, J. D. Violin, J. A. Stiber, P. B. Rosenberg, R. T. Premont, T. M. Coffman, H. A. Rockman, and R. J. Lefkowitz beta-Arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes PNAS, October 31, 2006; 103(44): 16284 - 16289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Smith, T. Rahman, N. Toohey, J. Mazurkiewicz, K. Herrick-Davis, and M. Teitler Risperidone Irreversibly Binds to and Inactivates the h5-HT7 Serotonin Receptor Mol. Pharmacol., October 1, 2006; 70(4): 1264 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Drake, S. K. Shenoy, and R. J. Lefkowitz Trafficking of G Protein-Coupled Receptors Circ. Res., September 15, 2006; 99(6): 570 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Morgan, D. M. Kristensen, D. Mittelman, and O. Lichtarge ET viewer: an application for predicting and visualizing functional sites in protein structures Bioinformatics, August 15, 2006; 22(16): 2049 - 2050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Violin, X.-R. Ren, and R. J. Lefkowitz G-protein-coupled Receptor Kinase Specificity for beta-Arrestin Recruitment to the beta2-Adrenergic Receptor Revealed by Fluorescence Resonance Energy Transfer J. Biol. Chem., July 21, 2006; 281(29): 20577 - 20588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dahan, A. Yassen, R. Romberg, E. Sarton, L. Teppema, E. Olofsen, and M. Danhof Buprenorphine induces ceiling in respiratory depression but not in analgesia Br. J. Anaesth., May 1, 2006; 96(5): 627 - 632. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |