Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β

Behrens, Jürgen; Jerchow, Boris; Würtele, Martin; Grimm, Jan; Asbrand, Christian; Wirtz, Ralph M.; Kühl, Michael; Wedlich, Doris; Birchmeier, Walter

doi:10.1126/science.280.5363.596

Cited by 1,160 publications

(1,034 citation statements)

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“…Moreover, we have shown that the regulators of G protein signaling (RGS) domain of rAxin interacts directly with APC, and that expression of rAxin in COS or SW480 cells stimulates the degradation of b-catenin (Kishida et al, , 1999a. Several groups have also reported the similar results (Behrens et al, 1998;Hart et al, 1998;Itoh et al, 1998;Sakanaka et al, 1998;Hamada et al, 1999). Therefore, it appears that Axin downregulates bcatenin by binding to GSK-3b, b-catenin, and APC, and enhancing GSK-3b-dependent phosphorylation of b-catenin.…”

Section: Introductionmentioning

confidence: 53%

“…Axil has 44% amino acid identity with rAxin and inhibits Xwnt-8-induced axis formation of Xenopus embryos like Axin . Conductin has been identi®ed as a b-catenin binding protein (Behrens et al, 1998) and found to be identical with Axil. We have found that both Axin and Axil bind to not only GSK-3b but also b-catenin directly, and that they promote GSK-3b-dependent phosphorylation of b-catenin .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 53%

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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“…Wnt-1 has been shown to regulate free pools of catenin (Papko et al, 1996) and both axin and the axin homologue conductin have been reported to alter b-catenin activity through interaction with Apc, b-catenin and GSK3b (Behrens et al, 1998;Ikeda et al, 1998;Kishida et al, 1998). The potential relevance of increased levels of b-catenin becomes clear in the light of ®ndings which show that b-catenin functionally interacts with and activates members of the Tcf family of DNA binding transcription factors, including both Lef-1 and Tcf 4 (Behrens et al, 1998;Korinek et al, 1997). Activation of transcriptional signalling by b-catenin-Tcf complexes has been shown to occur as a consequence of mutations in both Apc and b-catenin Rubinfeld et al, 1997) and mutations of bcatenin have been reported in human colorectal cancers (Sparks et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Kongkanuntn¹,

Bubb²,

Sansom³

et al. 1999

Oncogene

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We have analysed the pattern of b-catenin expression by immunohistochemistry in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased expression of b-catenin in all intestinal lesions arising on an Apc Min +/7 background. In all categories of lesion studied mosaic patterns of b-catenin expression were observed, with the proportion of cells showing enhanced expression decreasing with increasing lesion size. p53 status did not alter these patterns. We also show that bcatenin dysregulation marks pancreatic abnormalities occurring in Apc Min +/7 and (Apc Min +/7, p537/7) mice. In these mice both adenomas and adenocarcinomas of the pancreas arose and were characterized by increased expression of b-catenin. We have extended these analyses to intestinal lesions arising in mice mutant for the mismatch repair gene Msh2. In these mice, increased expression of b-catenin was again observed. However, in contrast with Apc Min +/7 mice, a subset of lesions retained normal expression. Taken together, these ®ndings show that increased expression of b-catenin is an e cient marker of early neoplastic change in both murine intestine and pancreas in Apc mutant mice. However, we also show that dysregulation of b-catenin is not an obligate step in the development of intestinal lesions, and therefore that genetic events other than the loss of Apc function may initiate the transition from normal to neoplastic epithelium.

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“…In particular, cyclin D1 and c-Myc have been reported to act as downstream targets of ␤-catenin and stimulate cell proliferation. In the absence of Wnt signals, the cellular concentration of ␤-catenin is kept relatively low through interactions with other proteins, such as adenomatous polyposis coli (APC) protein (5), GSK3␤ (6) and axin (7), that are involved in the phosphorylation of ␤-catenin. This phosphorylated form of ␤-catenin is degraded by the ubiquitinproteasome system (8; Fig.…”

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confidence: 99%

Loss of Membranous Expression of β-Catenin Is Associated with Tumor Progression in Cutaneous Melanoma and Rarely Caused by Exon 3 Mutations

et al. 2002

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␤-Catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor-and lymphoid enhancer factor-regulated gene transcription. The level of ␤-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3␤ (GSK-3␤) phosphorylation sites of the ␤-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of ␤-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor ␤-catenin mutations; in vivo, however, cellular accumulation of ␤-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. ␤-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of ␤-catenin in these cases. Cellular expression of ␤-catenin was evaluated by immunohistochemistry and by reverse polymerase chain reaction ( Cell-cell interactions play a key role in morphogenesis and maintenance of cellular differentiation; important regulators of these processes are the cadherins and catenins, which are involved in both cell-cell adhesion and signal transduction. Cadherins are transmembrane glycoproteins that mediate homotypic, Ca ϩϩ -dependent cell-cell adhesion. Based on structural features, three subtypes of cadherins can be distinguished. E-cadherin is the major cadherin in epithelial cells, whereas Ncadherin is expressed mainly by mesenchymal cells. Melanocytes interact with epidermal keratinocytes via E-and P-cadherin (1, 2). The cytoplasmic domain of cadherins associates with a group of proteins, termed catenins (␣-, ␤-and ␥-catenin), that connect the cadherins to the cytoskeleton (3).Besides its involvement in cell-cell adhesion, ␤-catenin also functions as a downstream molecule in the Wnt/wingless signaling pathway, where it forms complexes with the T-cell factor (Tcf) family

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Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β

Cited by 1,160 publications

References 23 publications

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

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

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Loss of Membranous Expression of β-Catenin Is Associated with Tumor Progression in Cutaneous Melanoma and Rarely Caused by Exon 3 Mutations

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