Factors Affecting the Nuclear Localization of β‐Catenin in Normal and Malignant Tissue

Abstract

The canonical Wnt signaling pathway has been the focus of intensive research because of its frequent dysregulation in human cancers. Much of this has been directed towards the aberrant expression and/or activity of the central mediator of this pathway, β-catenin. In particular, the nuclear localization of β-catenin and subsequent inappropriate activation of TCF/LEF-mediated transcription appears to be an important process in both the establishment and maintenance of cancer stem cells. Despite this, the exact mechanisms controlling β-catenin nuclear localization in both normal and malignant cells are poorly understood. This prospect article brings together the many mechanisms previously reported to regulate the nuclear localization of β-catenin and how they are relevant to cancer.

High Ki67 expression is an independent good prognostic marker in colorectal cancer

“…This observation fits well with the known relationship of p53, β-catenin and Ki67 in cell proliferation 28–30. β-Catenin is a key factor of Wingless Int-1 (WNT) signalling, and nuclear translocation of β-catenin characterises cells with active WNT signalling 31. Active WNT signalling leads to enhanced cell proliferation and, thus, to elevated Ki67LI.…”

Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser552

“…It is increasingly recognized that ␤-catenin nuclear localization is the initiating and driving element in ␤-catenin signaling, and that this step is regulated independently of its stabilization (35). A number of previous studies demonstrated that GPCR activation regulates ␤-catenin function and localization, but the mechanism(s) involved remained incompletely defined (50).…”

“…The binding of Wnt ligands to their receptor Frizzled and coreceptor LRP5/6 inactivates the ␤-catenin destruction complex (13), thereby promoting ␤-catenin cellular accumulation and nuclear import, association with T-cell factor/lymphoid enhancer factor (TCF/ LEF) transcription factors, and activation of target genes (13,33,63). It is increasingly recognized that ␤-catenin nuclear localization is the initiating and driving element in ␤-catenin signaling, and that this step is regulated independently of its stabilization (35). While NH 2 -terminal phosphorylation of ␤-catenin targets it to degradation, phosphorylation at Ser 552 and Ser 675 promotes its dissociation from cell-cell contacts, induces its nuclear localization, and stimulates its transcriptional activity via Wnt-independent pathways (11,16,17,27,30,41,60,61).…”

Differential diagnosis of bladder versus colorectal adenocarcinoma: keratin 7 and GATA3 positivity in nuclear ß-catenin-negative glandular tumours defines adenocarcinoma of the bladder

“…Furthermore, ΔNp63 was expressed in the caudal gut endoderm and contributed to the stem/progenitor compartment of adult colorectal epithelium, which could also lead to (basaloid) squamous carcinoma of the anorectal mucosa 24. Another helpful marker for the differential diagnosis of BAC versus CAC is ß-catenin, a protein regulating cell adhesion and gene transcription mainly via the Wnt signalling pathway 25. Nuclear translocation of ß-catenin results from lacking cytoplasmic degradation of ß-catenin in tumours with a non-functional degradation complex, which includes APC (adenomatous polyposis coli-protein).…”