The APC Protein and E-cadherin Form Similar but Independent Complexes with α-Catenin, β-Catenin, and Plakoglobin

Rubinfeld, Bonnee; Souza, Brian; Albert, Iris; Munemitsu, Susan; Polakis, Paul

doi:10.1074/jbc.270.10.5549

Cited by 292 publications

(174 citation statements)

References 38 publications

(19 reference statements)

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“…Interestingly, the same amino acid substitution has been demonstrated at codon 41 in exon 3 of the β-catenin gene in 2 endometrial carcinoma tissues (Fukuchi et al, 1998). γ-catenin shares strong amino acid similarity with β-catenin, binds APC and Tcf, and exhibits signalling activity similar to that of β-catenin (Karnovsky and Klymkowsky, 1995;Rubinfeld et al, 1995;Sacco et al, 1995). γ-catenin mutation in H1726 cells might be involved in activation of the APC/β-catenin/Tcf signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

Mutations of the β - and γ -catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas

et al. 2001

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β-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator in the Wnt signalling pathway. Although recent investigations have been focused on the role of the adenomatous polyposis coli (APC)/ β-catenin/Tcf pathway in human tumorigenesis, there have been very few reports on mutations of the β-catenin gene in a variety of tumour types. Using PCR and single-strand conformational polymorphism analysis, we examined 93 lung, 9 breast, 6 kidney, 19 cervical and 7 ovarian carcinoma cell lines for mutations in exon 3 of the β-catenin gene. In addition, we tested these same samples for mutations in the NH 2 -terminal regulatory region of the γ-catenin gene. Mutational analysis for the entire coding region of β-catenin cDNA was also undertaken in 20 lung, 9 breast, 5 kidney and 6 cervical carcinoma cell lines. Deletion of most β-catenin coding exons was confirmed in line NCI-H28 (lung mesothelioma) and a silent mutation at codon 214 in exon 5 was found in HeLa (cervical adenocarcinoma). A missense mutation at codon 19 and a silent mutation at codon 28 in the NH 2 -terminal regulatory region of the γ-catenin gene were found in H1726 (squamous cell lung carcinoma) and H1048 (small cell lung carcinoma), respectively. Neither deletions nor mutations of these genes were detected in the other cell lines examined. These results suggest that β- and γ-catenins are infrequent mutational targets during development of human lung, breast, kidney, cervical and ovarian carcinomas. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Mutations of the β - and γ -catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas

et al. 2001

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“…The major aim of this study was to explore the di erences in the interaction of b-catenin and plakoglobin with the ubiquitin-mediated degradation machinery that could be responsible for their di erent turnover and signaling activity. Previous studies have demonstrated that plakoglobin, similar to b-catenin, can interact with the GSK/APC/Axin system that regulates b-catenin stability (Hulsken et al, 1994;Rubinfeld et al, 1995;Kodama et al, 1999). In principle, di erences in the interaction of the two catenins with the ubiquitin-proteasome system could be due to either di erential phosphorylation of the two proteins by the GSK/APC/Axin complex, or to di erent processing by the ubiquitin system.…”

Section: Discussionmentioning

confidence: 99%

“…b-TrCP and its Drosophila homolog Slimb were implicated in the regulation of wnt/wg signaling (Jiang and Struhl, 1998) and the DF-b-TrCP mutant, lacking the F-box, was shown to induce axis duplication in Xenopus (Marikawa and Elinson, 1998;Liu et al, 1999), and loss of function mutations in Slimb, induce the accumulation of armadillo in Drosophila (Jiang and Struhl, 1998). Plakoglobin is also capable of associating with the GSK/APC/Axin complex (Hulsken et al, 1994;Rubinfeld et al, 1995;Kodama et al, 1999), but its degradation by the ubiquitin-proteasome system is less pronounced than that of b-catenin , and its mode of interaction with the b-TrCP ubiquitin ligase was not determined.…”

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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“…The N-terminus contains an oligomerization domain followed by seven repeats of an Armadillo motif. The middle portion of APC contains three successive 15-amino acid (aa) repeats followed by seven related but distinct 20-aa repeats, both of which are able to bind independently to b-catenin (Su et al, 1993;Rubinfeld et al, 1993Rubinfeld et al, , 1995. Following the 20-aa repeats is a basic region, while the C-terminus has a S/ TXV motif that interacts with the PDZ domaincontaining human homolog Dlg (Matsumine et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

et al. 2000

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Axin forms a complex with adenomatous polyposis coli gene product (APC), glycogen synthase kinase-3b (GSK3b), and b-catenin through di erent binding sites and downregulates b-catenin. GSK-3b-dependent phosphorylation of APC-(1211-2075) which has the Axin-binding site was facilitated by Axin, but that of APC-(959-1338) which lacks the Axin-binding site was not. Axin-(298-506) or Axin-(298-832), which has the GSK-3b-and bcatenin-but not APC-binding sites, did not enhance GSK-3b-dependent phosphorylation of either APC-(1211-2075) or APC-(959-1338). Furthermore, b-catenin stimulated the phosphorylation of APC-(959-1338) and APC-(1211-2075) by GSK-3b in the presence of Axin. Consistent with these in vitro observations, expression of b-catenin or Axin in COS cells promoted an SDS gel band shift of APC. These results indicate that APC complexed with Axin is e ectively phosphorylated by GSK-3b and that b-catenin may modulate this phosphorylation. In addition, the heterodimeric form of protein phosphatase 2A (PP2A) directly bound to Axin, and PP2A complexed with Axin dephosphorylated APC phosphorylated by GSK-3b. Taken together, these results suggest that GSK-3b-dependent phosphorylation of APC can be modulated by b-catenin and PP2A complexed with Axin. Oncogene (2000) 19, 537 ± 545.

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The APC Protein and E-cadherin Form Similar but Independent Complexes with α-Catenin, β-Catenin, and Plakoglobin

Cited by 292 publications

References 38 publications

Mutations of the β - and γ -catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas

Mutations of the β - and γ -catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas

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

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

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