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Human Molecular Genetics Advance Access originally published online on March 30, 2005
Human Molecular Genetics 2005 14(10):1283-1292; doi:10.1093/hmg/ddi139
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Functional analysis of Peutz–Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity

Christelle Forcet1,{dagger}, Sandrine Etienne-Manneville2,{dagger}, Hélène Gaude1, Laurence Fournier1, Sébastien Debilly1, Marko Salmi3, Annette Baas4, Sylviane Olschwang5, Hans Clevers4 and Marc Billaud1,*

1Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS UMR 5201, Domaine Rockefeller, 8 avenue Rockefeller, 69373 Lyon, Cedex 08, France 2CNRS UMR 144, Institut Curie, Paris, France 3MediCity Research Laboratory, Turku University, Turku, Finland 4Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, Utrecht, The Netherlands 5INSERM U434, Institut Paoli-Calmettes, Marseille, France

* To whom correspondence should be addressed. Tel: +33 478777213; Fax: +33 478777220; Email: billaud{at}univ-lyon1.fr

Received December 21, 2004; Revised March 11, 2005; Accepted March 22, 2005

Germline mutations of the LKB1 gene are responsible for the cancer-prone Peutz–Jeghers syndrome (PJS). LKB1 encodes a serine–threonine kinase that acts as a regulator of cell cycle, metabolism and cell polarity. The majority of PJS missense mutations abolish LKB1 enzymatic activity and thereby impair all functions assigned to LKB1. Here, we have investigated the functional consequences of recurrent missense mutations identified in PJS and in sporadic tumors which map in the LKB1 C-terminal non-catalytic region. We report that these C-terminal mutations neither disrupt LKB1 kinase activity nor interfere with LKB1-induced growth arrest. However, these naturally occuring mutations lessened LKB1-mediated activation of the AMP-activated protein kinase (AMPK) and impaired downstream signaling. Furthermore, C-terminal mutations compromise LKB1 ability to establish and maintain polarity of both intestinal epithelial cells and migrating astrocytes. Consistent with these findings, mutational analysis reveals that the LKB1 tail exerts an essential function in the control of cell polarity. Overall, our results ascribe a crucial regulatory role to the LKB1 C-terminal region. Our findings further indicate that LKB1 tumor suppressor activity is likely to depend on the regulation of AMPK signaling and cell polarization.

{dagger}The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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