β-Arrestin 2: A Receptor-Regulated MAPK Scaffold for the Activation of JNK3

β-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of β-arrestin 2 u...

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Published in:	Science (American Association for the Advancement of Science) 2000-11, Vol.290 (5496), p.1574-1577
Main Authors:	McDonald, Patricia H., Chow, Chi-Wing, Miller, William E., Laporte, Stéphane A., Field, Michael E., Lin, Fang-Tsyr, Davis, Roger J., Lefkowitz, Robert J.
Format:	Article
Language:	eng
Subjects:	Agonists Angiotensin II - metabolism Angiotensin II - pharmacology Animals Antibodies Arrestins - genetics Arrestins - metabolism beta-Arrestin 2 beta-Arrestins Biochemistry Biological and medical sciences Brain Cell Line Cell Nucleus - metabolism Cell physiology Cellular immunity Coding COS Cells Cytosol - enzymology Cytosol - metabolism DNA Endosomes - enzymology Endosomes - metabolism Enzyme Activation Fundamental and applied biological sciences. Psychology Humans Libraries MAP Kinase Kinase 4 MAP Kinase Kinase Kinase 5 MAP Kinase Kinase Kinases - metabolism MAP Kinase Signaling System Mice Mitogen-Activated Protein Kinase 10 Mitogen-Activated Protein Kinase Kinases - metabolism Mitogen-Activated Protein Kinases - metabolism Molecular and cellular biology Mutation Phosphorylation Physiological regulation Protein isoforms Protein-Tyrosine Kinases - metabolism Proteins Proto-Oncogene Proteins c-jun - metabolism Rats Receptor, Angiotensin, Type 1 Receptors Receptors, Angiotensin - metabolism Recombinant Fusion Proteins - metabolism Scaffolds Signal transduction Transfection Two-Hybrid System Techniques Yeasts
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Summary:	β-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of β-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase 1 (ASK1) and mitogen-activated protein kinase (MAPK) kinase 4 were also found in complex with β-arrestin 2. Cellular transfection of β-arrestin 2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of β-arrestin 2 and active JNK3 to intracellular vesicles. Thus, β-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR.
ISSN:	0036-8075 1095-9203