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Distinct molecular forms of beta-catenin are targeted to adhesive or transcriptional complexes.

Gottardi CJ, Gumbiner BM - J. Cell Biol. (2004)

Bottom Line: The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of beta-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism.Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation.In contrast, the main cadherin-binding form of beta-catenin is a beta-catenin-alpha-catenin dimer, indicating that there is a distinct molecular form of beta-catenin that can interact with both the cadherin and alpha-catenin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. c-gottardi@northwestern.edu.

ABSTRACT
Beta-catenin plays essential roles in both cell-cell adhesion and Wnt signal transduction, but what precisely controls beta-catenin targeting to cadherin adhesive complexes, or T-cell factor (TCF)-transcriptional complexes is less well understood. We show that during Wnt signaling, a form of beta-catenin is generated that binds TCF but not the cadherin cytoplasmic domain. The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of beta-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation. In contrast, the main cadherin-binding form of beta-catenin is a beta-catenin-alpha-catenin dimer, indicating that there is a distinct molecular form of beta-catenin that can interact with both the cadherin and alpha-catenin. We propose that participation of beta-catenin in adhesion or Wnt signaling is dictated by the regulation of distinct molecular forms of beta-catenin with different binding properties, rather than simple competition between cadherins and TCFs for a single constitutive form. This model explains how cells can control whether beta-catenin is used independently in cell adhesion and nuclear signaling, or competitively so that the two processes are coordinated and interrelated.

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Multiple forms of β-catenin exist in cells. NH2-terminal phospho-β-catenin is well characterized and generated by the APC-Axin-GSK3β-CK1 complex (dashed line). Closed form of β-catenin is generated by Wnt signaling, perhaps through some of the same machinery (gray arrow). β-Catenin–α-catenin dimer is active for adhesion but not signaling. Open form binds both cadherin and TCF, and could explain how cadherin antagonizes β-catenin signaling in overexpression systems. The inactive form cannot participate in adhesion or signaling.
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fig9: Multiple forms of β-catenin exist in cells. NH2-terminal phospho-β-catenin is well characterized and generated by the APC-Axin-GSK3β-CK1 complex (dashed line). Closed form of β-catenin is generated by Wnt signaling, perhaps through some of the same machinery (gray arrow). β-Catenin–α-catenin dimer is active for adhesion but not signaling. Open form binds both cadherin and TCF, and could explain how cadherin antagonizes β-catenin signaling in overexpression systems. The inactive form cannot participate in adhesion or signaling.

Mentions: Based on our findings from this and previous reports, we propose that cells contain a number of distinct molecular forms of β-catenin (Fig. 9). Thus, although an organism like C. elegans controls the adhesive and signaling functions of β-catenin through expression of a multi-gene family, vertebrates regulate β-catenin functions by generating distinct molecular forms at the protein level. First, there is the well-known form of β-catenin that is phosphorylated at the NH2 terminus and is targeted for degradation (Fig. 9, phosphorylated; for review see Polakis, 1999). We reported previously a large pool of β-catenin in the SW480 tumor cell line that cannot bind to either TCF or cadherin, and provided evidence that this was an “inactive” form for both adhesion and signaling (Fig. 9; Gottardi et al., 2001). This form may be due, at least in part, to ICAT, a small 9-kD polypeptide that inhibits β-catenin binding to both TCF and cadherin (Gottardi and Gumbiner, 2004; Tago et al., 2000). Here, we provide evidence for a TCF-selective form of β-catenin that is targeted to transcription complexes (closed conformation), and a form that can target to adhesive complexes (β-catenin–α-catenin dimer). Although the latter form can interact with both the cadherin and TCF, there is evidence that α-catenin inhibits the transcriptional activity of β-catenin in the nucleus (Giannini et al., 2000), suggesting that this form is specific for adhesion functions. Finally, we postulate that cells can contain a form of β-catenin that is competent for both signaling and cadherin binding (open conformation) which is observed, for example, under long-term LiCl treatment (Fig. 5 A, lanes 14 and 15), and would explain the many cases in which cadherin expression inhibits the transcriptional activity of β-catenin (Heasman et al., 1994; Fagotto et al., 1996; Sanson et al., 1996; Orsulic et al., 1999; Shtutman et al., 1999; Gottardi et al., 2001).


Distinct molecular forms of beta-catenin are targeted to adhesive or transcriptional complexes.

Gottardi CJ, Gumbiner BM - J. Cell Biol. (2004)

Multiple forms of β-catenin exist in cells. NH2-terminal phospho-β-catenin is well characterized and generated by the APC-Axin-GSK3β-CK1 complex (dashed line). Closed form of β-catenin is generated by Wnt signaling, perhaps through some of the same machinery (gray arrow). β-Catenin–α-catenin dimer is active for adhesion but not signaling. Open form binds both cadherin and TCF, and could explain how cadherin antagonizes β-catenin signaling in overexpression systems. The inactive form cannot participate in adhesion or signaling.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172558&req=5

fig9: Multiple forms of β-catenin exist in cells. NH2-terminal phospho-β-catenin is well characterized and generated by the APC-Axin-GSK3β-CK1 complex (dashed line). Closed form of β-catenin is generated by Wnt signaling, perhaps through some of the same machinery (gray arrow). β-Catenin–α-catenin dimer is active for adhesion but not signaling. Open form binds both cadherin and TCF, and could explain how cadherin antagonizes β-catenin signaling in overexpression systems. The inactive form cannot participate in adhesion or signaling.
Mentions: Based on our findings from this and previous reports, we propose that cells contain a number of distinct molecular forms of β-catenin (Fig. 9). Thus, although an organism like C. elegans controls the adhesive and signaling functions of β-catenin through expression of a multi-gene family, vertebrates regulate β-catenin functions by generating distinct molecular forms at the protein level. First, there is the well-known form of β-catenin that is phosphorylated at the NH2 terminus and is targeted for degradation (Fig. 9, phosphorylated; for review see Polakis, 1999). We reported previously a large pool of β-catenin in the SW480 tumor cell line that cannot bind to either TCF or cadherin, and provided evidence that this was an “inactive” form for both adhesion and signaling (Fig. 9; Gottardi et al., 2001). This form may be due, at least in part, to ICAT, a small 9-kD polypeptide that inhibits β-catenin binding to both TCF and cadherin (Gottardi and Gumbiner, 2004; Tago et al., 2000). Here, we provide evidence for a TCF-selective form of β-catenin that is targeted to transcription complexes (closed conformation), and a form that can target to adhesive complexes (β-catenin–α-catenin dimer). Although the latter form can interact with both the cadherin and TCF, there is evidence that α-catenin inhibits the transcriptional activity of β-catenin in the nucleus (Giannini et al., 2000), suggesting that this form is specific for adhesion functions. Finally, we postulate that cells can contain a form of β-catenin that is competent for both signaling and cadherin binding (open conformation) which is observed, for example, under long-term LiCl treatment (Fig. 5 A, lanes 14 and 15), and would explain the many cases in which cadherin expression inhibits the transcriptional activity of β-catenin (Heasman et al., 1994; Fagotto et al., 1996; Sanson et al., 1996; Orsulic et al., 1999; Shtutman et al., 1999; Gottardi et al., 2001).

Bottom Line: The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of beta-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism.Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation.In contrast, the main cadherin-binding form of beta-catenin is a beta-catenin-alpha-catenin dimer, indicating that there is a distinct molecular form of beta-catenin that can interact with both the cadherin and alpha-catenin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. c-gottardi@northwestern.edu.

ABSTRACT
Beta-catenin plays essential roles in both cell-cell adhesion and Wnt signal transduction, but what precisely controls beta-catenin targeting to cadherin adhesive complexes, or T-cell factor (TCF)-transcriptional complexes is less well understood. We show that during Wnt signaling, a form of beta-catenin is generated that binds TCF but not the cadherin cytoplasmic domain. The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of beta-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation. In contrast, the main cadherin-binding form of beta-catenin is a beta-catenin-alpha-catenin dimer, indicating that there is a distinct molecular form of beta-catenin that can interact with both the cadherin and alpha-catenin. We propose that participation of beta-catenin in adhesion or Wnt signaling is dictated by the regulation of distinct molecular forms of beta-catenin with different binding properties, rather than simple competition between cadherins and TCFs for a single constitutive form. This model explains how cells can control whether beta-catenin is used independently in cell adhesion and nuclear signaling, or competitively so that the two processes are coordinated and interrelated.

Show MeSH
Related in: MedlinePlus