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First published online 23 November 2004
doi: 10.1242/jcs.01571
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Research Article |
1 MRC Protein Phosphorylation Unit, MSI/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland
2 Division of Molecular Physiology, MSI/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland
3 Division of Biological Chemistry and Molecular Microbiology, MSI/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland
4 Division of Cell Biology and Immunology, MSI/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland
5 Sez, Genetica Medica DIMIMP, Università di Bari, Piazza G. Cesare 11, 70124 Bari, Italy
* Author for correspondence (e-mail: d.r.alessi{at}dundee.ac.uk)
Accepted 30 September 2004
Mutations in the LKB1 tumour suppressor threonine kinase cause the inherited Peutz-Jeghers cancer syndrome and are also observed in some sporadic cancers. Recent work indicates that LKB1 exerts effects on metabolism, polarity and proliferation by phosphorylating and activating protein kinases belonging to the AMPK subfamily. In vivo, LKB1 forms a complex with STRAD, an inactive pseudokinase, and MO25, an armadillo repeat scaffolding-like protein. Binding of LKB1 to STRAD-MO25 activates LKB1 and re-localises it from the nucleus to the cytoplasm. To learn more about the inherent properties of the LKB1-STRAD-MO25 complex, we first investigated the activity of 34 point mutants of LKB1 found in human cancers and their ability to interact with STRAD and MO25. Interestingly, 12 of these mutants failed to interact with STRAD-MO25. Performing mutagenesis analysis, we defined two binding sites located on opposite surfaces of MO25
, which are required for the assembly of MO25 into a complex with STRAD and LKB1. In addition, we demonstrate that LKB1 does not require phosphorylation of its own T-loop to be activated by STRAD-MO25, and discuss the possibility that this unusual mechanism of regulation arises from LKB1 functioning as an upstream kinase. Finally, we establish that STRAD, despite being catalytically inactive, is still capable of binding ATP with high affinity, but that this is not required for activation of LKB1. Taken together, our findings reinforce the functional importance of the binding of LKB1 to STRAD, and provide a greater understanding of the mechanism by which LKB1 is regulated and activated through its interaction with STRAD and MO25.
Key words: Peutz-Jeghers syndrome, AMPK, Pseudokinase, Cancer and Cell polarity
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