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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: We show that during Wnt signaling, a form of beta-catenin is generated that binds TCF but not the cadherin cytoplasmic domain.Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation.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.

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: We show that during Wnt signaling, a form of beta-catenin is generated that binds TCF but not the cadherin cytoplasmic domain.Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation.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.

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