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J. Biol. Chem., Vol. 283, Issue 22, 14946-14954, May 30, 2008

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Investigating the Regulation of Brain-specific Kinases 1 and 2 by Phosphorylation^*

From the Medical Research Council (MRC) Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London W12 0NN, United Kingdom

Brain-specific kinases 1 and 2 (BRSK1/2) are AMP-activated protein kinase (AMPK)-related kinases that are highly expressed in mammalian forebrain. Studies using transgenic animal models have implicated a role for these kinases in the establishment of neuronal polarity. BRSK1 and BRSK2 are activated by phosphorylation of a threonine residue in the T-loop activation segment of the kinase domain. In vitro studies have demonstrated that LKB1, an upstream kinase in the AMPK cascade, can catalyze this phosphorylation. However, to date, a detailed comparative analysis of the molecular regulation of BRSK1/2 has not been undertaken. Here we present evidence that excludes another upstream kinase in the AMPK cascade, Ca²⁺/calmodulin-dependent protein kinase kinase β, from a role in activating BRSK1/2. We show that equivalent mutations in the ubiquitin-associated domains of the BRSK isoforms produce differential effects on the activation of BRSK1 and BRSK2. Contrary to previous reports, activation of cAMP-dependent protein kinase does not affect BRSK1 or BRSK2 activity in mammalian cells. Furthermore, stimuli that activate AMPK had no effect on BRSK1/2. Finally, we provide evidence suggesting that protein phosphatase 2C is a likely candidate for catalyzing the dephosphorylation and inactivation of BRSK1/2.

Received for publication, December 20, 2007 , and in revised form, March 13, 2008.

^* This work was supported in part by the MRC UK, the European Commission (LSHM-CT-2004-005272 and LSH-CT-2005-518181) (to D. C.) and Research into Ageing (C. T.). 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.

¹ Recipient of an MRC-funded Ph.D. studentship.

² To whom correspondence may be addressed. Tel.: 44-20-8383-4313; Fax: 44-20-8383-8514; E-mail: dcarling{at}imperial.ac.uk. ³ To whom correspondence may be addressed. Tel.: 44-20-8383-4313; Fax: 44-20-8383-8514; E-mail: claire.thornton{at}imperial.ac.uk.

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