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J. Biol. Chem. 273 (2): 685-688

© 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

Essential Role for G Protein-coupled Receptor Endocytosis in the Activation of Mitogen-activated Protein Kinase*

Yehia Daaka, Louis M. Luttrell{ddagger}, Seungkirl Ahn, Gregory J. Della Rocca§, Stephen S. G. Ferguson, Marc G. Caron, , and Robert J. Lefkowitz

From the Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

ABSTRACT Back to Top

Abstract: The classical paradigm for G protein-coupled receptor (GPCR) signal transduction involves the agonist-dependent interaction of GPCRs with heterotrimeric G proteins at the plasma membrane and the subsequent generation, by membrane-localized effectors, of soluble second messengers or ion currents. Termination of GPCR signals follows G protein-coupled receptor kinase (GRK)- and β-arrestin-mediated receptor uncoupling and internalization. Here we show that these paradigms are inadequate to account for GPCR-mediated, Ras-dependent activation of the mitogen-activated protein (MAP) kinases Erk1 and -2. In HEK293 cells expressing dominant suppressor mutants of β-arrestin or dynamin, β2-adrenergic receptor-mediated activation of MAP kinase is inhibited. The inhibitors of receptor internalization specifically blocked Raf-mediated activation of MEK. Plasma membrane-delimited steps in the GPCR-mediated activation of the MAP kinase pathway, such as tyrosine phosphorylation of Shc and Raf kinase activation by Ras, are unaffected by inhibitors of receptor internalization. Thus, GRKs and β-arrestins, which uncouple GPCRs and target them for internalization, function as essential elements in the GPCR-mediated MAP kinase signaling cascade.

Received for publication October 6, 1997. Revision received November 4, 1997.


* This work was supported in part by National Institutes of Health Grant HL16037 (to R. J. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} Recipient of a National Institutes of Health Clinical Investigator Development Award.

§ Supported by National Institutes of Health MSTP Grant T32GM-07171.

To whom correspondence should be addressed. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}

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Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress.
G. Esposito, A. Rapacciuolo, S. V. Naga Prasad, H. Takaoka, S. A. Thomas, W. J. Koch, and H. A. Rockman (2002)
Circulation 105, 85-92
   Abstract »    Full Text »    PDF »
The Intersectin 2 Adaptor Links Wiskott Aldrich Syndrome Protein (WASp)-mediated Actin Polymerization to T Cell Antigen Receptor Endocytosis.
M. K.H. McGavin, K. Badour, L. A. Hardy, T. J. Kubiseski, J. Zhang, and K. A. Siminovitch (2001)
J. Exp. Med. 194, 1777-1787
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Cutting Edge: Differential Regulation of Chemoattractant Receptor-Induced Degranulation and Chemokine Production by Receptor Phosphorylation.
J. Ahamed, B. Haribabu, and H. Ali (2001)
J. Immunol. 167, 3559-3563
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Nerve Growth Factor Stimulation of p42/p44 Mitogen-Activated Protein Kinase in PC12 Cells: Role of Gi/o, G Protein-Coupled Receptor Kinase 2, {beta}-Arrestin I, and Endocytic Processing.
S. Rakhit, S. Pyne, and N. J. Pyne (2001)
Mol. Pharmacol. 60, 63-70
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Dopamine D4 and D2L Receptor Stimulation of the Mitogen-Activated Protein Kinase Pathway Is Dependent ontrans-Activation of the Platelet-Derived Growth Factor Receptor.
J. N. Oak, N. Lavine, and H. H. M. Van Tol (2001)
Mol. Pharmacol. 60, 92-103
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Regulation of Epidermal Growth Factor Receptor Signaling by Endocytosis and Intracellular Trafficking.
P. Burke, K. Schooler, and H. S. Wiley (2001)
Mol. Biol. Cell 12, 1897-1910
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Overexpression of N-Acetylglucosaminyltransferase III Enhances the Epidermal Growth Factor-induced Phosphorylation of ERK in HeLaS3 Cells by Up-regulation of the Internalization Rate of the Receptors.
Y. Sato, M. Takahashi, Y. Shibukawa, S. K. Jain, R. Hamaoka, J.-i. Miyagawa, Y. Yaginuma, K. Honke, M. Ishikawa, and N. Taniguchi (2001)
J. Biol. Chem. 276, 11956-11962
   Abstract »    Full Text »    PDF »
Differential Roles of the NPXXY Motif in Formyl Peptide Receptor Signaling.
R. He, D. D. Browning, and R. D. Ye (2001)
J. Immunol. 166, 4099-4105
   Abstract »    Full Text »    PDF »
Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling.
S. S. G. Ferguson (2001)
Pharmacol. Rev. 53, 1-24
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Requirement of cortical actin organization for bombesin, endothelin, and EGF receptor internalization.
J. A. Lunn, H. Wong, E. Rozengurt, and J. H. Walsh (2000)
Am J Physiol Cell Physiol 279, C2019-C2027
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Role of Phosphoinositide 3-Kinase and Endocytosis in Nerve Growth Factor-Induced Extracellular Signal-Regulated Kinase Activation via Ras and Rap1.
R. D. York, D. C. Molliver, S. S. Grewal, P. E. Stenberg, E. W. McCleskey, and P. J. S. Stork (2000)
Mol. Cell. Biol. 20, 8069-8083
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Phosphorylation of Phosducin and Phosducin-like Protein by G Protein-coupled Receptor Kinase 2.
A. Ruiz-Gomez, J. Humrich, C. Murga, U. Quitterer, M. J. Lohse, and F. Mayor Jr. (2000)
J. Biol. Chem. 275, 29724-29730
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Intersectin Can Regulate the Ras/MAP Kinase Pathway Independent of Its Role in Endocytosis.
X.-K. Tong, N. K. Hussain, A. G. Adams, J. P. O'Bryan, and P. S. McPherson (2000)
J. Biol. Chem. 275, 29894-29899
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Tales from the Crypt: Evidence for Heptahelical Receptor Signaling in the Endocytic Pathway.
J. Whistler, E. Beattie, and M. von Zastrow (2000)
Sci. STKE 2000, pe1
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{beta}2-Adrenergic Receptor Activates Extracellular Signal-regulated Kinases (ERKs) via the Small G Protein Rap1 and the Serine/Threonine Kinase B-Raf.
J. M. Schmitt and P. J. S. Stork (2000)
J. Biol. Chem. 275, 25342-25350
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The Recruitment of Raf-1 to Membranes Is Mediated by Direct Interaction with Phosphatidic Acid and Is Independent of Association with Ras.
M. A. Rizzo, K. Shome, S. C. Watkins, and G. Romero (2000)
J. Biol. Chem. 275, 23911-23918
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The Platelet-Derived Growth Factor Receptor Stimulation of p42/p44 Mitogen-Activated Protein Kinase in Airway Smooth Muscle Involves a G-Protein-Mediated Tyrosine Phosphorylation of Gab1.
S. Rakhit, S. Pyne, and N. J. Pyne (2000)
Mol. Pharmacol. 58, 413-420
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{beta}3- and {alpha}1-Adrenergic Erk1/2 Activation Is Src- but Not Gi-mediated in Brown Adipocytes.
J. M. Lindquist, J. M. Fredriksson, S. Rehnmark, B. Cannon, and J. Nedergaard (2000)
J. Biol. Chem. 275, 22670-22677
   Abstract »    Full Text »    PDF »

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