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

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.

Mucosal Pigmentation Caused by Imatinib: Report of Three Cases

“…Gsa gene mutation and cAMPmediated tyrosine kinase activation in melanocytes may play important roles in the formation of pigmented lesions in Albright syndrome [25]. In Peutz-Jegher syndrome, it is suggested that the pigmented lesions develop secondary to the mutation of the LKB1 gene, which activates the Wnt/bcatenin pathway and contributes to the stimulation of melanocytes [26], thereby causing the excess production of melanin. Addison disease represents primary adrenocortical insufficiency, stimulating the expression of ACTH and a-MSH similar to the estrogen-induced pigmentation mentioned previously.…”

LKB1; linking cell structure and tumor suppression

“…In contrast, other studies have indicated that Lkb1 downregulates the b-catenin pathway through either activation of GSK3-a negative regulator of b-catenin-or through diverting MARK2/ Par1a from its capacity to activate the pathway (Spicer et al, 2003;Lin-Marq et al, 2005). Although these observations are intriguing, the direct functional role of LKB1 in WNT signaling in vivo remains to be established.…”

“…However, in other cell types, levels of downstream AKT signaling do not appear to be regulated by LKB1 (Corradetti et al, 2004;Shaw et al, 2004a). Wnt/b-catenin signaling is also modulated by Lkb1 (Ossipova et al, 2003;Spicer et al, 2003;Lin-Marq et al, 2005). One report suggested that Lkb1 acts at a level upstream of GSK3 to upregulate b-catenin activity (Ossipova et al, 2003).…”

Lkb1 is required for TGFβ-mediated myofibroblast differentiation

“…These results support the previous report arguing sufficiency of TGFβ in inducing both the early and later phases of myofibroblast differentiation (Vaughan, 2000) as opposed to a role for PDGF in the early phases. In this regard, it is interesting to note that LKB1 overexpression was sufficient to increase expression of both PAI1 and SM22 in HeLa cells (Lin-Marq et al, 2005), indicating that LKB1 expression alone is sufficient to trigger expression of a TGFβ target gene (PAI1) and a myofibroblast marker gene (SM22) in epithelial cells directly.…”