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PMID:15731909

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Citation

Lin-Marq, N, Borel, C and Antonarakis, SE (2005) Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling. Mol. Genet. Genomics 273:184-96

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-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.

Links

PubMed Online version:10.1007/s00438-005-1124-y

Keywords

Cytoskeletal Proteins/metabolism; Flow Cytometry; Gene Expression Regulation; Genetic Vectors; Glycogen Synthase Kinase 3/metabolism; HeLa Cells; Humans; Immunoblotting; Intercellular Signaling Peptides and Proteins/metabolism; Lentivirus; Luciferases/metabolism; Mutation/genetics; Oligonucleotide Array Sequence Analysis; Peutz-Jeghers Syndrome/genetics; Peutz-Jeghers Syndrome/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/physiology; Trans-Activators/metabolism; Transfection; Wnt Proteins; beta Catenin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:STK11

involved_in

GO:0032147: activation of protein kinase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

RAT:STK11

involved_in

GO:0006470: protein dephosphorylation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

RAT:STK11

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

HUMAN:STK11

involved_in

GO:0032147: activation of protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P49841)

Seeded From UniProt

complete

HUMAN:STK11

involved_in

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P49841)

Seeded From UniProt

complete

HUMAN:STK11

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:STK11

involved_in

GO:0006470: protein dephosphorylation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

MOUSE:STK11

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

CHICK:STK11

involved_in

GO:0006470: protein dephosphorylation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

CHICK:STK11

involved_in

GO:0032147: activation of protein kinase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete

CHICK:STK11

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q15831

P

Seeded From UniProt

complete


See also

References

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