Lysine Residues Lys-19 and Lys-49 of β-Catenin Regulate Its Levels and Function in T Cell Factor Transcriptional Activation and Neoplastic Transformation

Winer, Ira; Bommer, Guido T.; Gonik, Nathan; Fearon, Eric R.

doi:10.1074/jbc.m604217200

Cited by 48 publications

(59 citation statements)

References 26 publications

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“…The activation of the SCF ␤-TrCP depends on the presence or absence of a Wnt ligand, whereas Siah-1-mediated ␤-catenin degradation is induced by activation of p53 during genotoxic stress. In the SCF ␤-TrCP complex, ␤-TrCP binds the phosphorylated N-terminal domain of ␤-catenin leading to the attachment of ubiquitin chains on Lys 19 and Lys 49 (47,48). Here, we show that Siah-1 binds the non-phosphorylated ␤-catenin, leading to the attachment of ubiquitin chains at the very C-terminal region of the (arm) domain on Lys 666 and Lys 671 .…”

Section: ␤-Catenin Ubiquitination By Siah-1 Protection By Tbl1mentioning

confidence: 81%

Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1

Dimitrova

Lee

et al. 2010

Journal of Biological Chemistry

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␤-Catenin is a key component of the Wnt signaling pathway that functions as a transcriptional co-activator of Wnt target genes. Upon UV-induced DNA damage, ␤-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin ␤-like 1 (TBL1), and adenomatous polyposis coli (APC). Given the complexity of the various factors involved and the novelty of ubiquitination of the non-phosphorylated ␤-catenin substrate, we have investigated Siah-1-mediated ubiquitination of ␤-catenin in vitro and in cells. Overexpression and purification protocols were developed for each of the SCF(TBL1) proteins, enabling a systematic analysis of ␤-catenin ubiquitination using an in vitro ubiquitination assay. This study revealed that Siah-1 alone was able to polyubiquitinate ␤-catenin. In addition, TBL1 was shown to play a role in protecting ␤-catenin from Siah-1 ubiquitination in vitro and from Siah-1-targeted proteasomal degradation in cells. Siah-1 and TBL1 were found to bind to the same armadillo repeat domain of ␤-catenin, suggesting that polyubiquitination of ␤-catenin is regulated by competition between Siah-1 and TBL1 during Wnt signaling.

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Section: ␤-Catenin Ubiquitination By Siah-1 Protection By Tbl1mentioning

confidence: 81%

Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1

Dimitrova

Lee

et al. 2010

Journal of Biological Chemistry

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“…It has been shown that the K19/K49 double mutant form of ␤-catenin is stabilized as a result of reduced ␤TrCP-dependent ubiquitination (Winer et al, 2006). According to the above-mentioned results, it is possible that K19 and K49 of ␤-catenin are involved in regulating its stability by PCAF.…”

Section: K19 and K49 Of ␤-Catenin Are Important For Its Acetylation Amentioning

confidence: 93%

“…␤-Catenin is usually degraded by ubiquitin proteasome system, and Lys-19 and Lys-49 are important sites for ␤-catenin ubiquitination (Aberle et al, 1997;Winer et al, 2006). Single amino acid substitutions of either Lys-19 or Lys-49 of ␤-catenin slightly affect its ubiquitination, but the K19/K49 double mutant ␤-catenin is stabilized as a result of significant reduced ␤TrCP-dependent ubiquitination (Winer et al, 2006). These findings implied that other posttranslational modifications at Lys-19 and Lys-49, such as acetylation, might affect the ubiquitination and stability of ␤-catenin.…”

Section: Discussionmentioning

confidence: 99%

“…The plasmid ␤-catenin-hemagglutinin (HA) was kindly provided by Dr. Lin Li (Shanghai Institutes for Biological Sciences, Shanghai, China; Pan et al, 2005). The wild-type (WT)-␤-catenin, K19R-␤-catenin, K49R-␤-catenin, K19,49R-␤-catenin cDNAs kindly provided by Dr. Eric R. Fearon (University of Michigan, Ann Arbor, MI; Winer et al, 2006) were subcloned into pCMV-Tag3B vector and pCX-PCAF-FLAG expression FLAG-tagged PCAF and pCX-⌬HAT 2 -PCAF-FLAG expressing PCAF with deletion of amino acids 608 -623 were provided by Dr. Xiang-Jiao Yang (McGill University, Montreal, Canada) as described previously (Yang et al, 1996;Zhao et al, 2003). pCMV-PCAF-Myc and pCMV-⌬HAT 2 -PCAF-Myc expressing Myc-tagged PCAF or ⌬HAT 2 -PCAF were obtained by insertion of PCAF cDNA fragment cut out with KpnI (blunted with Klenow fragment) and EcoRI from pCX-PCAF-FLAG or pCX-⌬HAT 2 -PCAF-FLAG into pCMV-Tag 3A (Stratagene, La Jolla, CA) at EcoRV and EcoRI sites.…”

Section: Plasmidsmentioning

confidence: 99%

“…Besides phosphorylation, ubiquitination and acetylation have also been reported to be involved in Wnt signaling (Aberle et al, 1997;Sun et al, 2000;Takemaru and Moon, 2000;Winer et al, 2006). Lys-19 and Lys-49 of ␤-catenin were reported as important ubiquitination sites (Winer et al, 2006), and Lys-49 of ␤-catenin was also reported to be acetylated by CBP (Wolf et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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PCAF Acetylates β-Catenin and Improves Its Stability

Jin

Zhang

et al. 2009

MBoC

104

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␤-Catenin plays an important role in development and tumorigenesis. However, the effect of a key acetyltransferase p300/CBP-associated factor (PCAF) on ␤-catenin signaling is largely unknown. In this study, we found PCAF could increase the ␤-catenin transcriptional activity, induce its nuclear translocation, and up-regulate its protein level by inhibiting its ubiquitination and improving its stability. Further studies showed that PCAF directly binds to and acetylates ␤-catenin. The key ubiquitination sites Lys-19 and Lys-49 of ␤-catenin were shown as the critical residues for PCAF-induced acetylation and stabilization. Knockdown of PCAF in colon cancer cells markedly reduced the protein level, transcriptional activity, and acetylation level of ␤-catenin; promoted cell differentiation; inhibited cell migration; and repressed xenografted tumorigenesis and tumor growth in nude mice. All these data demonstrate that PCAF acetylates ␤-catenin and regulates its stability, and they raise the prospect that therapies targeting PCAF may be of clinical use in ␤-catenin-driven diseases, such as colon cancer. INTRODUCTIONThe Wnt signaling pathway has important roles in a variety of developmental processes (Logan and Nusse, 2004;Clevers, 2006). The key output of this pathway is the stabilization and nuclear translocation of ␤-catenin, which determines the activation of ␤-catenin-responsive genes. Aberrant activation of Wnt signaling is often associated with carcinogenesis. Colorectal tumors are among most common human neoplasms, and Ͼ90% of colorectal cancers have a mutation that activates Wnt signaling (Giles et al., 2003;Doucas et al., 2005). Inactivating adenomatous polyposis coli (APC) mutations has been demonstrated in ϳ85% of sporadic colorectal tumors. Among the 15% colon carcinomas without APC mutations, ␤-catenin or the scaffolding protein Axin2 is mutant (Morin et al., 1997;Liu et al., 2000). Accumulating studies strongly suggest that disruption of Wnt signaling is a promising strategy for the prevention of colon cancers, and how to regulate the stability of ␤-catenin is the key point (Clapper et al., 2004;Dihlmann and von Knebel Doeber, 2005; DvorySobol et al., 2006).It is well known that Wnt signaling is regulated by phosphorylation. Besides phosphorylation, ubiquitination and acetylation have also been reported to be involved in Wnt signaling (Aberle et al., 1997;Sun et al., 2000;Takemaru and Moon, 2000;Winer et al., 2006). Lys-19 and Lys-49 of ␤-catenin were reported as important ubiquitination sites (Winer et al., 2006), and Lys-49 of ␤-catenin was also reported to be acetylated by CBP (Wolf et al., 2002). Whether there is some cross-talk between the ubiquitination and acetylation of ␤-catenin is yet to be elucidated. Some acetyltransferases such as CREB-binding protein (CBP)/p300 are related to colon cancer causation and progression (Muraoka et al., 1996;Ionov et al., 2004), and CBP/p300 can interact with ␤-catenin and synergistically activate ␤-catenin/T cell factor (TCF) transcription (Sun et al., 2000;Takema...

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WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway

et al. 2016

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The stability of β‐catenin is very important for canonical Wnt signaling. A protein complex including Axin/APC/GSK3β phosphorylates β‐catenin to be degraded by ubiquitination with β‐TrCP. In the recent study, we isolated WDR26, a protein that binds to Axin. Here, we found that WDR26 is a negative regulator of the canonical Wnt signaling pathway, and that WDR26 affected β‐catenin levels. In addition, WDR26/Axin binding is involved in the ubiquitination of β‐catenin. These results suggest that WDR26 plays a negative role in β‐catenin degradation in the Wnt signaling pathway.

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Lysine Residues Lys-19 and Lys-49 of β-Catenin Regulate Its Levels and Function in T Cell Factor Transcriptional Activation and Neoplastic Transformation

Cited by 48 publications

References 26 publications

Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1

Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1

PCAF Acetylates β-Catenin and Improves Its Stability

WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway

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