title: Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Medicine, Duke University Medical Center, Box 3821, Durham, NC 27710, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: McDonald
authors.forename: C W
authors.initials: CW
authors.lastname: Chow
authors.forename: W E
authors.initials: WE
authors.lastname: Miller
authors.forename: S A
authors.initials: SA
authors.lastname: Laporte
authors.forename: M E
authors.initials: ME
authors.lastname: Field
authors.forename: F T
authors.initials: FT
authors.lastname: Lin
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.forename: R J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D016755:Proto-Oncogene Proteins c-jun; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D011993:Recombinant Fusion Proteins; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000804:Angiotensin II; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases