Binding of GSK3β to the APC-β-Catenin Complex and Regulation of Complex Assembly

Rubinfeld, Bonnee; Albert, Iris; Porfiri, Emilio; Fiol, Carol J.; Munemitsu, Susan; Polakis, Paul

doi:10.1126/science.272.5264.1023

Cited by 1,346 publications

(1,061 citation statements)

References 26 publications

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“…In patients linked to familial adenomatous polyposis, truncations of or mutations in the APC gene are believed to enhance the progression of colorectal or gastric tumours, presumably through stabilisation of b-catenin in the cytoplasm (Rubinfeld et al, 1996). In the present study, APC expression was demonstrated in normal ovaries and benign tumours, but was low or absent in malignant ovarian tumours.…”

Section: Discussionsupporting

confidence: 44%

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

et al. 2003

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Beta-catenin is involved in both cell -cell adhesion and in transcriptional regulation by the Wingless/Wnt signalling pathway. Alterations of components of this pathway have been suggested to play a central role in tumorigenesis. The present study investigated, by immunohistochemistry and immunoblotting, the protein expression and localisation of b-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3b (GSK3b) and lymphocyte enhancer factor-1 (Lef-1) in normal human ovaries and in epithelial ovarian tumours in vivo and in vitro. Immortalised human ovarian surface epithelium and ovarian cancer cell cells (OVCAR-3) expressed b-catenin, APC, GSK3b and Lef-1. Nuclear staining of b-catenin and Lef-1 were demonstrated only in OVCAR-3 cells. There were significant increases of b-catenin and GSK3b, while APC was reduced in ovarian cancer compared to the normal ovary. Beta-catenin and Lef-1 were coimmunoprecipitated in ovarian tumours, but not in the normal ovary. Nuclear localisation of b-catenin or Lef-1 could not be demonstrated in the normal ovary or in the ovarian tumours. The absence of nuclear localisation of b-catenin could be due to an increased binding to the cadherin -a-catenin cell adhesion complex. In fact, we have earlier reported an increased expression of E-cadherin in ovarian adenocarcinomas. In summary, this study demonstrates an increase in the expression of components of the Wingless/Wnt pathway in malignant ovarian tumours. The increase suggests a role for this signalling pathway in cell transformation and in tumour progression. However, it remains to be demonstrated whether it is an increased participation of b-catenin in transcriptional regulation, or in the stabilisation of cellular integrity, or both, that is the crucial event in ovarian tumorigenesis.

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Section: Discussionsupporting

confidence: 44%

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

et al. 2003

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“…The latter complexes with glycogen synthase 3␤ (GSK-3␤) and thus controls degradation of ␤-catenin. Mutations of the APC gene or the ␤-catenin gene itself can thus result in the nuclear accumulation of ␤-catenin protein (42,43). Because ␤-catenin is a component of the wnt-signaling pathway controlling cell proliferation, its unregulated accumulation leads ultimately to unchecked cell proliferation and neoplasia.…”

Section: Discussionmentioning

confidence: 99%

Superficial Fibromatoses are Genetically Distinct from Deep Fibromatoses

et al. 2001

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“…The targeting of b-catenin for degradation involves the phosphorylation of its N-terminus by glycogen synthase kinase 3b (GSK) (Aberle et al, 1997;Yost et al, 1996) which occurs in a multi-protein complex consisting of b-catenin, GSK, the adenoma-tous polyposis coli (APC) tumor suppressor protein and axin/conductin Rubinfeld et al, 1996;Zeng et al, 1997;Ikeda et al, 1998;Behrens et al, 1998;Yamamoto et al, 1998). This complex associates with the ubiquitin ligase, b-TrCP (b-transducin repeat-containing protein) that recognizes the N-terminally phosphorylated forms of bcatenin and regulates its ubiquitination and degradation by the proteasome (Winston et al, 1999;Liu et al, 1999;Latres et al, 1999;Hart et al, 1999;Kitagawa et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

et al. 2000

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b-Catenin and plakoglobin are closely related armadillo family proteins with shared and distinct properties; Both are associated with cadherins in actin-containing adherens junctions. Plakoglobin is also found in desmosomes where it anchors intermediate ®laments to the desmosomal plaques. b-Catenin, on the other hand, is a component of the Wnt signaling pathway, which is involved in embryonic morphogenesis and tumorigenesis. A key step in the regulation of this pathway involves modulation of b-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of bcatenin and its degradation by the ubiquitin-proteasome system. Plakoglobin can also associate with members of this complex, but inhibition of proteasomal degradation has little e ect on its levels while dramatically increasing the levels of b-catenin. b-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of b-catenin. To elucidate the basis for the apparent di erences in the turnover of bcatenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of b-TrCP, lacking the F-box, can stabilize the endogenous b-catenin leading to its nuclear translocation and induction of b-catenin/ LEF-1-directed transcription, without a ecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with b-TrCP, e ciently competed with b-catenin for binding to b-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of b-catenin. These results suggest that while both plakoglobin and b-catenin can comparably interact with b-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.

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Binding of GSK3β to the APC-β-Catenin Complex and Regulation of Complex Assembly

Cited by 1,346 publications

References 26 publications

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

Superficial Fibromatoses are Genetically Distinct from Deep Fibromatoses

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

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