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β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

Oncogene volume 25, pages 218–229 (2006)Cite this article

Abstract

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 β-arrestins was investigated. β-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 β-arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR β2 subtype showed the strongest sensitivity to β-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 β2 receptor through which β-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 β2 transcriptional activation in a β-arrestin 2- and ERK2-dependent manner.

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Acknowledgements

We thank M Ader for cloning the retinoid receptors. The β-arrestin constructs were kindly provided by G Pei. We are also indebted to M Karin and T Deng for the JNK1, ERK2 and p38 constructs.

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  1. ACADIA Pharmaceuticals Inc., San Diego, 92121, CA, USA

    F Piu, N K Gauthier & F Wang

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  1. F Piu
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Correspondence to F Piu.

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Piu, F., Gauthier, N. & Wang, F. β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase. Oncogene 25, 218–229 (2006). https://doi.org/10.1038/sj.onc.1209024

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