Human Molecular Genetics Advance Access published online on March 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi139
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS UMR 5201, Domaine Rockefeller, 8 avenue Rockefeller, Lyon
* To whom correspondence should be addressed. 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 do not 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 signalling. 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 tumour suppressor activity is likely to depend on the regulation of AMPK signalling and cell polarization.
Article
Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 carboxy-terminal region exerts a crucial role in regulating both the AMPK pathway and cell polarity
2 CNRS UMR 144, Institut Curie, Paris
3 MediCity Research Laboratory, Turku University, Turku, Finland
4 Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, Utrecht, The Netherlands
5 INSERM U434, Institut Paoli-Calmettes, Marseille
6 Laboratoire Génétique et Cancer, UMR5201 CNRS, Domaine Rockefeller, 8, avenue Rockefeller, 69373 Lyon Cedex 08, France
Marc Billaud, E-mail: billaud{at}univ-lyon1.fr
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Xie, Y. Dong, J. Zhang, R. Scholz, D. Neumann, and M.-H. Zou Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis Mol. Cell. Biol., July 1, 2009; 29(13): 3582 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Caramel, F. Quignon, and O. Delattre RhoA-Dependent Regulation of Cell Migration by the Tumor Suppressor hSNF5/INI1 Cancer Res., August 1, 2008; 68(15): 6154 - 6161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. B. Pearson, A. McCarthy, C. M.P. Collins, A. Ashworth, and A. R. Clarke Lkb1 Deficiency Causes Prostate Neoplasia in the Mouse Cancer Res., April 1, 2008; 68(7): 2223 - 2232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, Y. Dong, R. Scholz, D. Neumann, and M.-H. Zou Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-{zeta} Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells Circulation, February 19, 2008; 117(7): 952 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, K. Schafer-Hales, F. R. Khuri, W. Zhou, P. M. Vertino, and A. I. Marcus The Tumor Suppressor LKB1 Regulates Lung Cancer Cell Polarity by Mediating cdc42 Recruitment and Activity Cancer Res., February 1, 2008; 68(3): 740 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Riboulet-Chavey, F. Diraison, L. K. Siew, F. S. Wong, and G. A. Rutter Inhibition of AMP-Activated Protein Kinase Protects Pancreatic {beta}-Cells From Cytokine-Mediated Apoptosis and CD8+ T-Cell-Induced Cytotoxicity Diabetes, February 1, 2008; 57(2): 415 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Forcet and M. Billaud Dialogue Between LKB1 and AMPK: A Hot Topic at the Cellular Pole Sci. Signal., September 18, 2007; 2007(404): pe51 - pe51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Partanen, A. I. Nieminen, T. P. Makela, and J. Klefstrom Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization PNAS, September 11, 2007; 104(37): 14694 - 14699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, J. Li, L. H. Young, and M. J. Caplan AMP-activated protein kinase regulates the assembly of epithelial tight junctions PNAS, November 14, 2006; 103(46): 17272 - 17277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marshall Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer Sci. Signal., August 1, 2006; 2006(346): re7 - re7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Volikos, J Robinson, K Aittomaki, J-P Mecklin, H Jarvinen, A M Westerman, F W M de Rooji, T Vogel, G Moeslein, V Launonen, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome. J. Med. Genet., May 1, 2006; 43(5): e18 - e18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, Y. Dong, M. Zhang, M.-Z. Cui, R. A. Cohen, U. Riek, D. Neumann, U. Schlattner, and M.-H. Zou Activation of Protein Kinase C{zeta} by Peroxynitrite Regulates LKB1-dependent AMP-activated Protein Kinase in Cultured Endothelial Cells J. Biol. Chem., March 10, 2006; 281(10): 6366 - 6375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Rattan, S. Giri, A. K. Singh, and I. Singh 5-Aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside Inhibits Cancer Cell Proliferation in Vitro and in Vivo via AMP-activated Protein Kinase J. Biol. Chem., November 25, 2005; 280(47): 39582 - 39593. [Abstract] [Full Text] [PDF]
|
|