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

Science  24 Nov 2000:
Vol. 290, Issue 5496, pp. 1574-1577
DOI: 10.1126/science.290.5496.1574

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Abstract

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.

  • * These authors contributed equally to this work.

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