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Molecular Genetics and Genomics

, Volume 273, Issue 2, pp 184–196 | Cite as

Peutz–Jeghers LKB1 mutants fail to activate GSK-3β, preventing it from inhibiting Wnt signaling

  • Nathalie Lin-Marq
  • Christelle Borel
  • Stylianos E. AntonarakisEmail author
Original Paper

Abstract

Peutz–Jeghers syndrome (PJS) is caused by germline mutations in the LKB1 gene, which encodes a serine-threonine kinase that regulates cell proliferation and polarity. This autosomal dominant disorder is characterized by mucocutaneous melanin pigmentation, multiple gastrointestinal hamartomatous polyposis and an increased risk of developing various neoplasms. To understand the molecular pathogenesis of PJS phenotypes, we used microarrays to analyze gene expression profiles in proliferating HeLa cells transduced with lentiviral vectors expressing wild type or mutant LKB1 proteins. We show that gene expression is differentially affected by mutations that impair the kinase activity (K78I) or alter the cellular localization of the LKB1 protein. However, both mutations abrogate the ability of LKB1 to up-regulate the transcription of several genes involved in Wnt signaling, including DKK3, WNT5B and FZD2. In addition—and in contrast to the wild type protein—these LKB1 mutants fail to activate the GSK-3β kinase, which otherwise phosphorylates β-catenin. The increase in β-catenin phosphorylation that occurs upon expression of wild-type LKB1 results in transcriptional inhibition of a canonical Wnt reporter gene. This suggests that pathogenic LKB1 mutations that lead to activation of the Wnt/β-catenin pathway could contribute to the cancer predisposition of PJS patients.

Keywords

Peutz–Jeghers syndrome (PJS) LKB1 Wnt signaling β-Catenin 

Notes

Acknowledgements

We thank Dr. P. Descombes, Dr. M. Docquier, Dr. D. Chollet and Dr. O. Schaad, members of the NCCR genomic platform of the University of Geneva, for assistance in microarray and real-time RT-PCR analysis; Dr. C. Chaponnier (University of Geneva, Switzerland) for her kind gift of TAGLN antibodies, Dr. M. Neerman-Arbez, Dr. A. Reymond and Dr. R. Lyle for their critical reading of the manuscript; Dr. R. Moon for the gift of TOPflash/FOPflash vectors. N.L.M was supported by the Swiss National Science Foundation and the S.E.A laboratory was supported by grants from the Swiss Cancer League.

Supplementary material

438_2005_1124_ESM_supp.pdf (301 kb)
(PDF 302 KB)

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Nathalie Lin-Marq
    • 1
  • Christelle Borel
    • 1
  • Stylianos E. Antonarakis
    • 1
    Email author
  1. 1.Department of Genetics Medicine and DevelopmentUniversity of Geneva Medical SchoolGeneve 4Switzerland

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