Beta-arrestin 2 modulates the activity of nuclear receptor RAR beta2 through activation of ERK2 kinase.
The activity of retinoid receptors activity can be regulated by various extracellular stimuli. In an effort to understand the molecular basis for this phenomenon, the role of beta-arrestins was investigated. Beta-Arrestins constitute a class of proteins involved in the internalization of agonist-activated receptors. They have also been linked to MAPK activation suggesting a direct involvement in signaling cascades. Here, we report that beta-arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR beta2 subtype showed the strongest sensitivity to beta-arrestin 2 action. Interestingly, this event requires the presence of the MAP kinase ERK2, but not that of JNK or P38. Site-directed mutagenesis showed that Ser 22 and Leu 217 are critical residues of the RAR beta2 receptor through which beta-arrestin 2 effects are mediated. More importantly, we demonstrate that the induction of PC12 growth inhibition by Nerve Growth Factor is indeed dependent upon RAR beta2 transcriptional activation in a beta-arrestin 2- and ERK2-dependent manner.
Piu
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ACADIA Pharmaceuticals Inc., San Diego, CA 92121, USA. fpiu@acadia-pharm.com
Gauthier
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Wang
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D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007930:Leucine / Q000737:chemistry / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D018168:Receptors, Retinoic Acid; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C082925:retinoic acid receptor beta; D012694:Serine; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D007930:Leucine