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

Publication ,  Journal Article
Lin-Marq, N; Borel, C; Antonarakis, SE
Published in: Mol Genet Genomics
April 2005

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-3beta kinase, which otherwise phosphorylates beta-catenin. The increase in beta-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/beta-catenin pathway could contribute to the cancer predisposition of PJS patients.

Duke Scholars

Published In

Mol Genet Genomics

DOI

ISSN

1617-4615

Publication Date

April 2005

Volume

273

Issue

2

Start / End Page

184 / 196

Location

Germany

Related Subject Headings

  • beta Catenin
  • Wnt Proteins
  • Transfection
  • Trans-Activators
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases
  • Plant Biology & Botany
  • Phosphorylation
  • Peutz-Jeghers Syndrome
 

Citation

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Lin-Marq, N., Borel, C., & Antonarakis, S. E. (2005). Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling. Mol Genet Genomics, 273(2), 184–196. https://doi.org/10.1007/s00438-005-1124-y
Lin-Marq, Nathalie, Christelle Borel, and Stylianos E. Antonarakis. “Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling.Mol Genet Genomics 273, no. 2 (April 2005): 184–96. https://doi.org/10.1007/s00438-005-1124-y.
Lin-Marq N, Borel C, Antonarakis SE. Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling. Mol Genet Genomics. 2005 Apr;273(2):184–96.
Lin-Marq, Nathalie, et al. “Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling.Mol Genet Genomics, vol. 273, no. 2, Apr. 2005, pp. 184–96. Pubmed, doi:10.1007/s00438-005-1124-y.
Lin-Marq N, Borel C, Antonarakis SE. Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling. Mol Genet Genomics. 2005 Apr;273(2):184–196.
Journal cover image

Published In

Mol Genet Genomics

DOI

ISSN

1617-4615

Publication Date

April 2005

Volume

273

Issue

2

Start / End Page

184 / 196

Location

Germany

Related Subject Headings

  • beta Catenin
  • Wnt Proteins
  • Transfection
  • Trans-Activators
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases
  • Plant Biology & Botany
  • Phosphorylation
  • Peutz-Jeghers Syndrome