ArticleMolecular genetics and genomics : MGG2005
Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling.
Article in Molecular genetics and genomics : MGG, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 48 citations in OpenAlex.
- Article
- LKB1 biology: assessing the therapeutic relevancy of LKB1 inhibitors.Cell communication and signaling : CCS · 2024Review
- Involvement of NADPH Oxidase 1 in Liver Kinase B1-Mediated Effects on Tumor Angiogenesis and Growth.Frontiers in oncology · 2018Article
- Specific deletion of LKB1/Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Loss of liver kinase B1 causes planar polarity defects in cochlear hair cells in mice.Frontiers of medicine · 2016Article
- GSK-3β controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells.The Prostate · 2016Article
- LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2014Article
- The tumor suppressor LKB1 antagonizes WNT signaling pathway through modulating GSK3β activity in cell growth of esophageal carcinoma.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014Article
- Two variants in STK11 gene in Chinese patients with Peutz-Jeghers syndrome.Journal of genetics · 2012Article
- Mucosal pigmentation caused by imatinib: report of three cases.Head and neck pathology · 2012Article
- Endopancreatic bile duct cholangiocarcinoma in a patient with peutz-jeghers syndrome.HPB surgery : a world journal of hepatic, pancreatic and biliary surgery · 2011Article
- Immunohistological evidence for Wnt-signaling activation in Peutz-Jeghers polyposis.Pediatric surgery international · 2010Article
- LKB1; linking cell structure and tumor suppression.Oncogene · 2008Review
- Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung.Carcinogenesis · 2008Article
- LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome.Journal of medical genetics · 2006Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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