Wnt-1 Regulates Free Pools of Catenins and Stabilizes APC-Catenin Complexes

Papkoff, Jackie; Rubinfeld, Bonnee; Schryver, Brian; Polakis, Paul

doi:10.1128/mcb.16.5.2128

Cited by 303 publications

(258 citation statements)

References 30 publications

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“…Stable expression of several Wnt genes, including Wnt-1 and Wnt-3a, stabilizes b-catenin in mammalian cells (Hinck et al, 1994;Papko et al, 1996;Shimizu et al, 1997). We also observed soluble Wnt-3a proteins secreted into the culture medium have the same action on b-catenin (Shibamoto et al, 1999).…”

Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

“…It has been demonstrated that b-catenin accumulates in SW480 human colorectal cancer cells of which APC is truncated and in AtT20 mouse pituitary and C57MG mouse mammary epithelial cells expressing Wnt-1 and that the low molecular weight complexed b-catenin on gel ®ltration column chromatography increases in these cells (Munemitsu et al, 1995;Papko et al, 1996). When the extracts of wild-type L cells were applied to a gel ®ltration column, most of the b-catenin eluted with a peak at fractions 17/18 (high molecular weight complex), while a small amount of b-catenin eluted with a peak at fraction 26/27 (low molecular weight complex) (Figure 4).…”

Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

“…Furthermore, expression of rAxin resulted in a reduction in the high molecular weight complexed b-catenin (Figure 4). It has been shown that expression of APC inhibits the accumulation of bcatenin induced by expression of Wnt-1 in both the high and low molecular weight complexes (Papko et al, 1996) and abrogates the transcription activity of hTcf-4 Morin et al, 1997). Therefore, the mode of action of Axin in the degradation of b-catenin may be similar to that of APC.…”

Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

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Axin prevents Wnt-3a-induced accumulation of β-catenin

et al. 1999

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When Axin, a negative regulator of the Wnt signaling pathway, was expressed in COS cells, it coeluted with glycogen synthase kinase-3b (GSK-3b), b-catenin, and adenomatous polyposis coli protein (APC) in a high molecular weight fraction on gel ®ltration column chromatography. In this fraction, GSK-3b, b-catenin, and APC were co-precipitated with Axin. Although bcatenin was detected in the high molecular weight fraction in L cells on gel ®ltration column chromatography, addition of conditioned medium expressing Wnt3a to the cells increased b-catenin in the low molecular weight fraction. However, Wnt-3a-dependent accumulation of b-catenin was greatly inhibited in L cells stably expressing Axin. Axin also suppressed Wnt-3a-dependent activation of Tcf-4 which binds to b-catenin and acts as a transcription factor. These results suggest that Axin forms a complex with GSK-3b, b-catenin, and APC, resulting in the stimulation of the degradation of bcatenin and that Wnt-3a induces the dissociation of bcatenin from the Axin complex and accumulates bcatenin.

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Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

Section: E Ect Of Raxin On Wnt-3a-induced Accumulation Of B-cateninmentioning

confidence: 99%

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Axin prevents Wnt-3a-induced accumulation of β-catenin

et al. 1999

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“…When the APC protein binds to b-catenin, it promotes the phosphorylation of highly conserved serine and threonine residues in bcatenin's NH2 terminus by GSK-3, thereby targeting b-catenin for degradation via the proteosome system (Papko et al, 1996;Orford et al, 1997). Loss of APC function results in nuclear accumulation of b-catenin, which acts as a transcriptional activator by binding to the Tcf ± Lef (T cell factor/lymphoid enhancer factor) family of transcription factors, ultimately leading to loss of cellular growth control (Morin et al, 1997;Sparks et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

et al. 2000

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The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

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“…The binding of wnt to its receptor frizzled, results in the inhibition of GSK activity (Cook et al, 1996) and a subsequent elevation in b-catenin level (Papko et al, 1996). This is followed by the translocation of bcatenin into the nucleus and its interaction with LEF/ TCF family transcription factors (Behrens et al, 1996;Huber et al, 1996;Molenaar et al, 1996), leading to the transactivation of LEF/TCF-responsive target genes (Molenaar et al, 1996;van de Wetering et al, 1997).…”

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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Wnt-1 Regulates Free Pools of Catenins and Stabilizes APC-Catenin Complexes

Cited by 303 publications

References 30 publications

Axin prevents Wnt-3a-induced accumulation of β-catenin

Axin prevents Wnt-3a-induced accumulation of β-catenin

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

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

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