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Molecular and Cellular Biology, December 2006, p. 9497-9507, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01099-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

BRF1 Protein Turnover and mRNA Decay Activity Are Regulated by Protein Kinase B at the Same Phosphorylation Sites{triangledown}

Don Benjamin,{dagger} Martin Schmidlin,{dagger} Lu Min, Brigitte Gross, and Christoph Moroni*

Institute for Medical Microbiology, Petersplatz 10, 4003 Basel, Switzerland

Received 19 June 2006/ Returned for modification 28 July 2006/ Accepted 28 September 2006

BRF1 posttranscriptionally regulates mRNA levels by targeting ARE-bearing transcripts to the decay machinery. We previously showed that protein kinase B (PKB) phosphorylates BRF1 at Ser92, resulting in binding to 14-3-3 and impairment of mRNA decay activity. Here we identify an additional regulatory site at Ser203 that cooperates in vivo with Ser92. In vitro kinase labeling and wortmannin sensitivity indicate that Ser203 phosphorylation is also performed by PKB. Mutation of both serines to alanine uncouples BRF1 from PKB regulation, leading to constitutive mRNA decay even in the presence of stabilizing signals. BRF1 protein is labile because of proteasomal degradation (half-life, <3 h) but becomes stabilized upon phosphorylation and is less stable in PKB{alpha}–/– cells. Surprisingly, phosphorylation-dependent protein stability is also regulated by Ser92 and Ser203, with parallel phosphorylation required at these sites. Phosphorylation-dependent binding to 14-3-3 is abolished only when both sites are mutated. Cell compartment fractionation experiments support a model in which binding to 14-3-3 sequesters BRF1 through relocalization and prevents it from executing its mRNA decay activity, as well as from proteasomal degradation, thereby maintaining high BRF1 protein levels that are required to reinstate decay upon dissipation of the stabilizing signal.

* Corresponding author. Mailing address: Institute for Medical Microbiology, Petersplatz 10, 4003 Basel, Switzerland. Phone: 41 61 2673264. Fax: 41 61 2673283. E-mail: christoph.moroni{at}unibas.ch.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} D.B. and M.S. contributed equally to this study.

Molecular and Cellular Biology, December 2006, p. 9497-9507, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01099-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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