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PNAS 98 (5): 2449-2454

Copyright © 2001 by the National Academy of Sciences.


Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds

Louis M. Luttrell*,{dagger},{ddagger}, Francine L. Roudabush{dagger}, Eric W. Choy{dagger}, William E. Miller§, Michael E. Field{dagger}, Kristen L. Pierce§, and Robert J. Lefkowitz{dagger},§

*The Geriatrics Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, Durham, NC 27705; and The Howard Hughes Medical Institute, and Departments of {dagger}Medicine and §Biochemistry, Box 3821, Duke University Medical Center, Durham, NC 27710

Contributed by Robert J. Lefkowitz

Accepted for publication December 18, 2000.

Abstract: Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of β-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a receptors (AT1aR). In HEK-293 cells expressing hemagglutinin-tagged AT1aR, angiotensin stimulation triggered β-arrestin-2 binding to the receptor and internalization of AT1aR-β-arrestin complexes. Using red fluorescent protein-tagged ERK2 to track the subcellular distribution of ERK2, we found that angiotensin treatment caused the redistribution of activated ERK2 into endosomal vesicles that also contained AT1aR-β-arrestin complexes. This targeting of ERK2 reflects the formation of multiprotein complexes containing AT1aR, β-arrestin-2, and the component kinases of the ERK cascade, cRaf-1, MEK1, and ERK2. Myc-tagged cRaf-1, MEK1, and green fluorescent protein-tagged ERK2 coprecipitated with Flag-tagged β-arrestin-2 from transfected COS-7 cells. Coprecipitation of cRaf-1 with β-arrestin-2 was independent of MEK1 and ERK2, whereas the coprecipitation of MEK1 and ERK2 with β-arrestin-2 was significantly enhanced in the presence of overexpressed cRaf-1, suggesting that binding of cRaf-1 to β-arrestin facilitates the assembly of a cRaf-1, MEK1, ERK2 complex. The phosphorylation of ERK2 in β-arrestin complexes was markedly enhanced by coexpression of cRaf-1, and this effect is blocked by expression of a catalytically inactive dominant inhibitory mutant of MEK1. Stimulation with angiotensin increased the binding of both cRaf-1 and ERK2 to β-arrestin-2, and the association of β-arrestin-2, cRaf-1, and ERK2 with AT1aR. These data suggest that β-arrestins function both as scaffolds to enhance cRaf-1 and MEK-dependent activation of ERK2, and as targeting proteins that direct activated ERK to specific subcellular locations.

{ddagger} To whom reprint requests should be addressed. E-mail: luttrell{at}

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Spatial regulation of Raf kinase signaling by RKTG.
L. Feng, X. Xie, Q. Ding, X. Luo, J. He, F. Fan, W. Liu, Z. Wang, and Y. Chen (2007)
PNAS 104, 14348-14353
   Abstract »    Full Text »    PDF »
A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction.
J. I. Aguirre, L. I. Plotkin, A. R. Gortazar, M. M. Millan, C. A. O'Brien, S. C. Manolagas, and T. Bellido (2007)
J. Biol. Chem. 282, 25501-25508
   Abstract »    Full Text »    PDF »
Receptor heterodimerization leads to a switch in signaling: {beta}-arrestin2-mediated ERK activation by {micro}-{delta} opioid receptor heterodimers.
R. Rozenfeld and L. A. Devi (2007)
FASEB J 21, 2455-2465
   Abstract »    Full Text »    PDF »
K. N. Nobles, Z. Guan, K. Xiao, T. G. Oas, and R. J. Lefkowitz (2007)
J. Biol. Chem. 282, 21370-21381
   Abstract »    Full Text »    PDF »
G-protein-coupled receptor expression, function, and signaling in macrophages.
J. Lattin, D. A. Zidar, K. Schroder, S. Kellie, D. A. Hume, and M. J. Sweet (2007)
J. Leukoc. Biol. 82, 16-32
   Abstract »    Full Text »    PDF »
Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation.
M. D. Willard, F. S. Willard, X. Li, S. D. Cappell, W. D. Snider, and D. P. Siderovski (2007)
EMBO J. 26, 2029-2040
   Abstract »    Full Text »    PDF »
Identification of a putative nuclear localization sequence within ANG II AT1A receptor associated with nuclear activation.
T. A. Morinelli, J. R. Raymond, A. Baldys, Q. Yang, M.-h. Lee, L. Luttrell, and M. E. Ullian (2007)
Am J Physiol Cell Physiol 292, C1398-C1408
   Abstract »    Full Text »    PDF »
beta-arrestin signaling and regulation of transcription.
L. Ma and G. Pei (2007)
J. Cell Sci. 120, 213-218
   Abstract »    Full Text »    PDF »
The IL Sequence in the LLKIL Motif in CXCR2 Is Required for Full Ligand-induced Activation of Erk, Akt, and Chemotaxis in HL60 Cells.
J. Sai, G. Walker, J. Wikswo, and A. Richmond (2006)
J. Biol. Chem. 281, 35931-35941
   Abstract »    Full Text »    PDF »
G Protein-coupled Receptor Kinase and beta-Arrestin-mediated Desensitization of the Angiotensin II Type 1A Receptor Elucidated by Diacylglycerol Dynamics.
J. D. Violin, S. M. DeWire, W. G. Barnes, and R. J. Lefkowitz (2006)
J. Biol. Chem. 281, 36411-36419
   Abstract »    Full Text »    PDF »
Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons.
T. A. Macey, J. D. Lowe, and C. Chavkin (2006)
J. Biol. Chem. 281, 34515-34524
   Abstract »    Full Text »    PDF »
CXCL12 Induces Tyrosine Phosphorylation of Cortactin, Which Plays a Role in CXC Chemokine Receptor 4-mediated Extracellular Signal-regulated Kinase Activation and Chemotaxis.
C. Luo, H. Pan, M. Mines, K. Watson, J. Zhang, and G.-H. Fan (2006)
J. Biol. Chem. 281, 30081-30093
   Abstract »    Full Text »    PDF »
R7BP Augments the Function of RGS7{middle dot}Gbeta5 Complexes by a Plasma Membrane-targeting Mechanism.
R. M. Drenan, C. A. Doupnik, M. Jayaraman, A. L. Buchwalter, K. M. Kaltenbronn, J. E. Huettner, M. E. Linder, and K. J. Blumer (2006)
J. Biol. Chem. 281, 28222-28231
   Abstract »    Full Text »    PDF »
Ubiquitin-dependent Down-regulation of the Neurokinin-1 Receptor.
G. S. Cottrell, B. Padilla, S. Pikios, D. Roosterman, M. Steinhoff, D. Gehringer, E. F. Grady, and N. W. Bunnett (2006)
J. Biol. Chem. 281, 27773-27783
   Abstract »    Full Text »    PDF »
Kermit 2/XGIPC, an IGF1 receptor interacting protein, is required for IGF signaling in Xenopus eye development.
J. Wu, M. O'Donnell, A. D. Gitler, and P. S. Klein (2006)
Development 133, 3651-3660
   Abstract »    Full Text »    PDF »
Arrestin Serves as a Molecular Switch, Linking Endogenous {alpha}2-Adrenergic Receptor to SRC-dependent, but Not SRC-independent, ERK Activation.
Q. Wang, R. Lu, J. Zhao, and L. E. Limbird (2006)
J. Biol. Chem. 281, 25948-25955
   Abstract »    Full Text »    PDF »
Visual and Both Non-visual Arrestins in Their "Inactive" Conformation Bind JNK3 and Mdm2 and Relocalize Them from the Nucleus to the Cytoplasm.
X. Song, D. Raman, E. V. Gurevich, S. A. Vishnivetskiy, and V. V. Gurevich (2006)
J. Biol. Chem. 281, 21491-21499
   Abstract »    Full Text »    PDF »
Localization of ERK/MAP Kinase Is Regulated by the Alphaherpesvirus Tegument Protein Us2.
M. G. Lyman, J. A. Randall, C. M. Calton, and B. W. Banfield (2006)
J. Virol. 80, 7159-7168
   Abstract »    Full Text »    PDF »
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".
F. Jafri, H. M. El-Shewy, M.-H. Lee, M. Kelly, D. K. Luttrell, and L. M. Luttrell (2006)
J. Biol. Chem. 281, 19346-19357
   Abstract »    Full Text »    PDF »
Kappa Opioid Receptor Activation of p38 MAPK Is GRK3- and Arrestin-dependent in Neurons and Astrocytes.
M. R. Bruchas, T. A. Macey, J. D. Lowe, and C. Chavkin (2006)
J. Biol. Chem. 281, 18081-18089
   Abstract »    Full Text »    PDF »
Cooperative Regulation of Extracellular Signal-Regulated Kinase Activation and Cell Shape Change by Filamin A and {beta}-Arrestins.
M. G. H. Scott, V. Pierotti, H. Storez, E. Lindberg, A. Thuret, O. Muntaner, C. Labbe-Jullie, J. A. Pitcher, and S. Marullo (2006)
Mol. Cell. Biol. 26, 3432-3445
   Abstract »    Full Text »    PDF »
Distinct beta-Arrestin- and G Protein-dependent Pathways for Parathyroid Hormone Receptor-stimulated ERK1/2 Activation.
D. Gesty-Palmer, M. Chen, E. Reiter, S. Ahn, C. D. Nelson, S. Wang, A. E. Eckhardt, C. L. Cowan, R. F. Spurney, L. M. Luttrell, et al. (2006)
J. Biol. Chem. 281, 10856-10864
   Abstract »    Full Text »    PDF »
Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism..
Q. Jiang, Z. Yan, and J. Feng (2006)
J. Neurosci. 26, 4318-4328
   Abstract »    Full Text »    PDF »
Nonvisual Arrestin Oligomerization and Cellular Localization Are Regulated by Inositol Hexakisphosphate Binding.
S. K. Milano, Y.-M. Kim, F. P. Stefano, J. L. Benovic, and C. Brenner (2006)
J. Biol. Chem. 281, 9812-9823
   Abstract »    Full Text »    PDF »

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