Abstract
beta-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 beta-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 beta-arrestin 2. Cellular transfection of beta-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 beta-arrestin 2 and active JNK3 to intracellular vesicles. Thus, beta-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiotensin II / metabolism
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Angiotensin II / pharmacology
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Animals
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Arrestins / genetics
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Arrestins / metabolism*
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COS Cells
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Cell Line
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Cell Nucleus / metabolism
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Cytosol / enzymology
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Cytosol / metabolism
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Endosomes / enzymology
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Endosomes / metabolism
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Enzyme Activation
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Humans
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MAP Kinase Kinase 4*
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System*
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Mice
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Mutation
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-jun / metabolism
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Rats
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Receptor, Angiotensin, Type 1
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Receptors, Angiotensin / metabolism*
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Recombinant Fusion Proteins / metabolism
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Transfection
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Two-Hybrid System Techniques
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beta-Arrestin 2
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beta-Arrestins
Substances
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ARRB2 protein, human
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Arrb2 protein, mouse
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Arrb2 protein, rat
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Arrestins
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Proto-Oncogene Proteins c-jun
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Receptor, Angiotensin, Type 1
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Receptors, Angiotensin
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Recombinant Fusion Proteins
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beta-Arrestin 2
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beta-Arrestins
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Angiotensin II
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Mitogen-Activated Protein Kinase 10
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Protein-Tyrosine Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases
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MAP3K5 protein, human
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Map3k5 protein, mouse
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MAP Kinase Kinase 4
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MAP2K4 protein, human
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Map2k4 protein, mouse
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Mitogen-Activated Protein Kinase Kinases