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J. Biol. Chem., Vol. 281, Issue 46, 35021-35029, November 17, 2006

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FRAT1, a Substrate-specific Regulator of Glycogen Synthase Kinase-3 Activity, Is a Cellular Substrate of Protein Kinase A^*

Thilo Hagen, Supported by a Marie Curie Industry Host Fellowship (awarded to A. D. R.) throughout the duration of this work¹, Darren A. E. Cross², Ainsley A. Culbert^¶, Andrew West^||, Sheelagh Frame^**3, Nick Morrice^**, and Alastair D. Reith^¶

From the Discovery Research Biology, ^¶Neurology Centre of Excellence in Drug Discovery, ^||Computational, Analytical, and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AD, United Kingdom, Medicines Research Centre, Stevenage, Herts SG1 2NY, United Kingdom, ^**Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom, and Wolfson Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2UH, United Kindom

FRAT1, like its Xenopus homolog glycogen synthase kinase-3 (GSK-3)-binding protein, is known to inhibit GSK-3-mediated phosphorylation of -catenin. It is currently unknown how FRAT-GSK-3-binding protein activity toward GSK-3 is regulated. FRAT1 has recently been shown to be a phosphoprotein in vivo; however, the responsible kinase(s) have not been determined. In this study, we identified Ser¹⁸⁸ as a phosphorylated residue in FRAT1. The identity of the kinase that catalyzes Ser¹⁸⁸ phosphorylation and the significance of this phosphorylation to FRAT1 function were investigated. Protein kinase A (PKA) was found to phosphorylate Ser¹⁸⁸ in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled -adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser¹⁸⁸. GSK-3 was also able to phosphorylate FRAT1 at Ser¹⁸⁸ and other residues in vitro or when overexpressed in intact cells. In contrast, endogenous GSK-3 did not lead to significant FRAT1 phosphorylation in cells, suggesting that GSK-3 is not a major FRAT1 kinase in vivo. Phosphorylation of Ser¹⁸⁸ by PKA inhibited the ability of FRAT1 to activate -catenin-dependent transcription. In conclusion, PKA phosphorylates FRAT1 in vitro as well as in intact cells and may play a role in regulating the inhibitory activity of FRAT1 toward GSK-3.

Received for publication, July 24, 2006 , and in revised form, September 15, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.

³ Present address: Cyclacel Ltd., James Lindsay Pl., Dundee, DD1 5JJ United Kingdom.

¹ To whom correspondence should be addressed. Tel.: 44-115-8231079; E-mail: Thilo.Hagen{at}nottingham.ac.uk.

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