title: Phosphorylation of β-catenin results in lack of β-catenin signaling in melanoma.
abstract: The Wnt/β-catenin pathway is involved in differentiation events during embryonic development and is further described as a pathway often participating in tumor formation when aberrantly activated. Molecular studies concentrating on colorectal cancer revealed mutations of apc, ctnnbi, btrc and tcf-4 genes which mimic Wnt stimulation. However, such mutations are rarely found during melanoma development. Therefore, we analyzed the β-catenin activity in this type of skin cancer. Interestingly, localization of β-catenin protein was basically cytoplasmic in melanomas in vivo, which was in clear contrast to findings in colon carcinoma. Congruently, the transcriptional activity of β-catenin regulating expression of β-catenin target genes was not observed in several melanoma cell lines. Further, neither LiCl nor Wnt agonist treatment led to significant activation of β-catenin signaling. This lack in functionality seems to depend on phosphorylation at threonine 41 and serine 45 of β-catenin observed in several melanoma cell lines. However, this specific endogenous phosphorylation pattern led to upregulation of other signaling pathways resulting e.g. in induction of N-cadherin expression. In summary, this study suggests a cell type-specific regulation of β-catenin function. This alternative β-catenin signaling pathway should be considered when thinking about targeting β-catenin in melanoma treatment.
authors.affiliation: University of Regensburg, Institute of Pathology, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. skuphal@gmx.de
authors.forename: Silke
authors.initials: S
authors.lastname: Kuphal
authors.forename: Anja Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008545:Melanoma / Q000503:physiopathology*; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin