The β-catenin protein, encoded by CTNNB1
, functions in both cell adhesion and transcription. In normal cells, β-catenin is mostly bound to cell membrane cadherins at adherens junctions, thus fulfilling its essential role in cell adhesion, and remaining sequestered from the nucleus and its growth-promoting role.(95
) Also β-catenin is a critical component of the Wnt signaling pathway, which is crucial during embryonal development and is also activated in various human cancers. The cellular abundance of β-catenin is constitutively down-regulated by proteasomal degradation. A multicomponent complex that includes APC (encoded by the APC
gene, which is inactivated in familial adenomatous polyposis) binds β-catenin and recruits two kinases, glycogen synthase kinase-3 (GSK) and casein kinase I, which phosphorylate β-catenin and target it for polyubiquitination and degradation by the proteasome. The Wnt signaling pathway stabilizes β-catenin by inhibiting its phosphorylation by GSK-3 and its subsequent proteosomal degradation, allowing β-catenin to translocate to the nucleus and function as a transcriptional Wnt effector.
The nuclear localization and transcriptional growth-promoting activity of β-catenin can be enhanced when its binding to cadherin is abolished (e.g. due to decreased cadherin expression), or when GSK3β-axin-APC-mediated targeting for degradation is defective (e.g. due to inactivating mutations in APC
, or by CTNNB1
mutations that disrupt phosphorylation sites and lead to protein stabilization), or by an overactive Wnt pathway.(96
) Germline mutations in the APC
gene are responsible for familial adenomatous polyposis (FAP) and its variant, Gardner syndrome, which confers a markedly increased risk of development of PTC.(97
E-cadherin expression is high in normal thyroid tissue, but decreased in undifferentiated thyroid carcinomas.(98
) Mutations of β-catenin, leading to nuclear localization of the protein, are present in poorly differentiated and anaplastic carcinomas (up to 25% and 65% respectively) but not in well-differentiated tumors.(99
) Thus, both loss of E-cadherin expression and acquisition of β-catenin mutations appear to be associated with thyroid carcinoma dedifferentiation and disease progression.