Characterization of an alternative splice variant of LKB1.
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 LKB1L) and a 48-kDa form (LKB1S). LKB1L is widely expressed in mouse tissues, whereas LKB1S has a restricted tissue distribution with predominant expression in the testis. LKB1S, like LKB1L, 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 LKB1L are not conserved in LKB1S 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 LKB1L activity and that both LKB1L and LKB1S 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.
Denison
Fiona C
FC
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.
Hiscock
Natalie J
NJ
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.
Carling
David
D
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. Electronic address: dcarling@imperial.ac.uk.
Woods
Angela
A
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. Electronic address: angela.woods@imperial.ac.uk.
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D017368:Protein Prenylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D022821:RNA Splice Sites / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D007527:Isoenzymes; D022821:RNA Splice Sites; C518004:STRAD protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases