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J. Biol. Chem., Vol. 284, Issue 1, 67-76, January 2, 2009

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Characterization of an Alternative Splice Variant of LKB1^*

Fiona C. Denison¹, Natalie J. Hiscock, David Carling², and Angela Woods³

From the Cellular Stress Group, Medical Research Council Clinical Sciences Centre, DuCane Road, London W12 0NN, United Kingdom and the Unilever Discover, Personalised Vitality Platform, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, United Kingdom

LKB1 is an upstream activating kinase for the AMP-activated protein kinase (AMPK) and at least 12 other AMPK-related kinases. LKB1 therefore acts as a master kinase regulating the activity of a wide range of downstream kinases, which themselves have diverse physiological roles. Here we identify a second form of LKB1 generated by alternative splicing of the LKB1 gene. The two LKB1 proteins have different C-terminal sequences generating a 50-kDa form (termed LKB1_L) and a 48-kDa form (LKB1_S). LKB1_L is widely expressed in mouse tissues, whereas LKB1_S has a restricted tissue distribution with predominant expression in the testis. LKB1_S, like LKB1_L, forms a complex with MO25 and STRAD, and phosphorylates and activates AMPK both in vitro and in intact cells. A phosphorylation site (serine 431 in mouse) and a farnesylation site (cysteine 433 in mouse) within LKB1_L are not conserved in LKB1_S raising the possibility that these sites might be involved in differential regulation and/or localization of the two forms of LKB1. However, we show that phosphorylation of serine 431 has no effect on LKB1_L activity and that both LKB1_L and LKB1_S have similar patterns of subcellular localization. These results indicate that the physiological significance of the different forms of LKB1 is not related directly to differences in the C-terminal sequences but may be due to their differential patterns of tissue distribution.

Received for publication, August 8, 2008 , and in revised form, October 9, 2008.

^* This work was supported by the Medical Research Council and European Commission Grants LSHM-CT-2004-005272 and LSH-CT-2005-518181 (to D. C.). 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 a Biotechnology and Biological Sciences Research Council-Collaborative Awards in Science and Engineering Ph. D. studentship with Unilever Discover UK.

² To whom correspondence may be addressed: Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London, W12 0NN, United Kingdom. Tel.: 44-20-8383-4313; Fax: 44-20-8383-8514; E-mail: dcarling{at}imperial.ac.uk. ³ To whom correspondence may be addressed: Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London, W12 0NN, United Kingdom. Tel.: 44-20-8383-4313; Fax: 44-20-8383-8514; E-mail: angela.woods{at}imperial.ac.uk.

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