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Article |
Correspondence to Cara J. Gottardi: c-gottardi{at}northwestern.edu
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Abstract |
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Introduction |
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Why might the cell use a single protein for both cellcell adhesion and nuclear signaling? One possibility is that signaling and adhesion are tightly coordinated through competition for a common pool of ß-catenin. Indeed, some evidence suggests that the signaling and adhesive pools of ß-catenin are interrelated in this way. Overexpression of cadherins in Xenopus and other systems can antagonize ß-catenin signaling activity (Heasman et al., 1994; Fagotto et al., 1996; Sanson et al., 1996; Orsulic et al., 1999), whereas reduction in the expression of cadherins in Drosophila embryos can enhance ß-catenin signaling (Cox et al., 1996). Although experimental manipulation of cadherin levels can affect ß-catenin nuclear signaling, it is not yet clear whether ß-catenin signaling in vivo is actually regulated by changes in endogenous cadherin levels or function. Moreover, there is also evidence that these two processes can occur largely independently of each other. For example, cadherin loss-of-function is not often associated with enhanced ß-catenin signaling (Caca et al., 1999; Vasioukhin et al., 2001), and Wnt activation does not typically alter cellcell adhesion, although enhanced adhesive activity has been reported previously (Bradley et al., 1993; Hinck et al., 1994). Thus, how the roles of ß-catenin in signaling and adhesion are controlled to be either coordinated or independent remains to be elucidated.
In the cases where expression of cadherins antagonizes ß-catenin nuclear signaling activity, inhibition occurs by direct binding of ß-catenin to the cytoplasmic domain of cadherins, and sequestration from the nuclear compartment (Fagotto et al., 1996; Orsulic et al., 1999; Shtutman et al., 1999; Gottardi et al., 2001). Recent evidence argues that the signaling and adhesive forms of ß-catenin may share molecularly similarities. For example, comparison of ß-catenincadherin and ß-cateninTCF cocrystal structures revealed that both ß-catenin ligands bind to extensively overlapping regions along ß-catenin, and in some regions engage identical residues (for review see Gottardi and Gumbiner, 2001). Given such similarity in binding mechanism between ß-catenincadherin and ß-cateninTCF complexes, we proposed that the cadherin is such a favorable inhibitor of ß-catenin nuclear signaling, not only because it sequesters ß-catenin away from the nucleus, but also because it can compete directly with TCF for ß-catenin binding (Gottardi and Gumbiner, 2001).
Nonetheless, the functions of ß-catenin can be molecularly distinct. For example, C. elegans uses three different ß-catenin gene products for adhesion and signaling functions (Korswagen et al., 2000). BAR-1 mediates Wnt signaling by forming a transcription complex with the TCF homologue, POP-1, whereas HMP-2 interacts exclusively with the cadherin gene product, HMR-1. WRM-1 is involved in a divergent Wnt pathway where it regulates POP-1 indirectly. Although this simple organism has evolved three distinct genes to segregate adhesive from signaling forms of ß-catenin, there is no evidence for multiple ß-catenin gene products in vertebrates. A splice variant of ß-catenin lacking the COOH-terminal transactivation domain has been identified in Drosophila, however, which seems to function only in adhesion (Loureiro and Peifer, 1998). Vertebrates, therefore, must somehow be able to rely on a single ß-catenin gene product for both adhesion and signaling functions.
The notion of a single molecular form of ß-catenin that participates identically in cell adhesion and gene expression seems to be over simplified. In SW480 tumor cells, a large fraction of ß-catenin was found to be refractory to both cadherin- and TCF-binding in vitro (Gottardi et al., 2001). This is due, at least in part, to the interaction of ß-catenin with a 9-kD polypeptide, ICAT (Tago et al., 2000), which can prevent ß-catenin binding to both TCF and cadherin proteins (Gottardi and Gumbiner, 2004). The small fraction of ß-catenin that can bind to TCF also can interact with the cadherin, which explains how cadherin expression inhibits ß-cateninTCF signaling and cell growth in this cell line (Gottardi et al., 2001). Thus, cells contain at least two distinct forms of ß-catenin, raising the possibility that the binding properties of ß-catenin may be regulated. These distinct forms were identified, however, in a tumor cell line harboring a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene product, which is known to deregulate the normal degradation of ß-catenin in cells. Therefore, we sought to examine the regulation of ß-catenin binding properties by its physiological regulator, Wnt.
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Results |
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To further determine the regions of ß-catenin control this binding selectivity, we also examined the binding properties of a series of ß-catenin deletion mutants expressed in cells. Full-length NH2-terminal myc-, or COOH-terminal flag-tagged ß-catenin exhibits preferential binding to TCF-GST relative to cad-GST when transfected into HEK293 cells incubated with Wnt3a-conditioned media (Fig. 3). Importantly, the level of exogenous ß-catenin expression needed to be kept low in order to detect ß-catenin binding selectivity (compare 0.2 µg with 2 µg plasmid), suggesting that the cellular machinery responsible for generating binding selectivity may be easily saturable. As a control, simply diluting the sample transfected with 2 µg plasmid by 10-fold, so that the ß-catenin levels were similar to those extracts transfected with 0.2 µg plasmid, did not result in differential binding (unpublished data), indicating that binding selectivity is due to an active cellular process. A construct bearing a deletion of the COOH terminus (hß-catC695) shows equivalent binding to both cadherin and TCF, consistent with a role for the COOH terminus in regulating binding selectivity. Curiously, however, deletion of both NH2- and COOH-terminal domains generates a protein that binds TCF significantly better than the cadherin, even at relatively high levels of expression (e.g., compare 3 µg plasmid for Xß-cat arm 12 with WTX-ß-cat 2 µg). It was recently proposed that the NH2-terminal region of ß-catenin may be required for efficient cadherin binding, as a GST-ß-catenin fusion protein missing the first 119 aa showed little cadherin binding activity in vitro (Castano et al., 2002). We also find that
89ß-catenin binds poorly to the cadherin compared with TCF, even at our highest expression levels (Fig. 3). Thus, we suggest that the NH2-terminal region of ß-catenin is required for cadherin but not TCF binding, which gives rise to apparent binding selectivity. When ß-catenin is able to bind the cadherin (i.e., when the NH2 terminus is present), however, the COOH terminus is required for generating ß-catenin binding selectivity.
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Effect of APC mutations, inhibition of GSK-3ß activity, NH2-terminal phosphorylation of ß-catenin, and cadherin phosphorylation on ß-catenin binding specificity
To explore the signaling pathways that might control these forms of ß-catenin, we sought to examine the role of the APC tumor suppressor gene product and glycogen synthase kinase (GSK)-3ß, two key components in the Wnt pathway, as well as the role of known phosphorylations of ß-catenin in response to Wnts. We examined several colon carcinoma cell lines that contain either wild-type or mutant forms of APC (Fig. 6 A). All of these cell lines manifest constitutive ß-catenin signaling due to inactivating mutations in APC (HT29, DLD1), or activating mutations within the GSK-3ß regulatory region of ß-catenin (HCT116). No differences in ß-catenin binding to cadherin- and TCF-GST fusion proteins were observed, suggesting that ß-catenin binding selectivity is not simply due to inhibition of APC-mediated destruction of ß-catenin. Interestingly, the role of GSK-3ß is more complex. Short-term inhibition of GSK3ß by lithium chloride (LiCl; under 4 h at 10 mM) mimics the Wnt effect on ß-catenin, i.e., ß-catenin preferentially binds TCF-GST greater than cad-GST (Fig. 6 B, lanes 1 and 2). Therefore, inhibition of GSK3ß activity alone is sufficient to mimic the effect of Wnt on ß-catenin binding activities. Curiously, however, long-term inhibition of GSK3ß by LiCl (over 6 h at 10 mM) generates a pool of ß-catenin that binds TCF and cadherin-GST proteins equally well (Fig. 6 B, lanes 36). Thus, more potent effects of LiCl do not mimic Wnt signaling, but instead result in the accumulation of high levels of ß-catenin with no binding specificity, similar to tumor cells with APC mutations. One interpretation of these two types of effects is that GSK might have multiple targets besides the NH2 terminus of ß-catenin (e.g., APC, Rubinfeld et al., 1996; or Axin, Jho et al., 1999). Alternatively, long-term incubation with LiCl could have pleiotropic effects on cell signaling pathways, or the cellular machinery that regulates ß-catenin binding to TCF versus cadherin may be easily saturable, so that differential binding is not observed when ß-catenin levels rise to unphysiological levels. This explanation is consistent with findings that total cytosolic levels of ß-catenin appear to increase substantially with the duration of LiCl treatment (Fig. 6 B, compare lanes 2, 4, and 6), and because expression levels via transfection give similar results (Fig. 3).
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Discussion |
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We provide evidence that the Wnt-stimulated, TCF-binding selectivity of ß-catenin is mediated by the COOH-terminal region of ß-catenin. First, COOH-terminal epitopes of ß-catenin are masked in the fraction of ß-catenin that is unable bind the cadherin. Second, a COOH-terminal peptide of ß-catenin can compete ß-catenin binding to cadherin, but not to TCF. Third, deletion of the COOH terminus of ß-catenin results in a loss of binding selectivity. Together with previously published data showing that the COOH-terminal region of ß-catenin can bind directly to the armadillo repeat region of ß-catenin (Cox et al., 1999; Piedra et al., 2001) and restrict cadherin binding in vitro (Castano et al., 2002), we propose that in vivo, the COOH terminus of ß-catenin adopts a folded-over conformation which controls ß-catenin binding selectivity by restricting cadherin but not TCF binding. Thus, Wnts may activate ß-catenin signaling not only by increasing its cytosolic levels, but by regulating the conformation of its COOH terminus.
The existence of a form of ß-catenin that distinguishes between cadherins and TCF was not anticipated, given the overall structural similarity between the ß-catenincadherin and ß-cateninTCF binding interfaces revealed by X-ray crystallography (Graham et al., 2000; Huber and Weis, 2001). Upon closer examination, however, the ß-cateninTCF binding interface is less extensive than the ß-catenincadherin binding interface, spanning arm repeats 310 compared with all 12 armadillo repeats for the cadherin. Thus, it is possible that the COOH-terminal region of ß-catenin may fold-back over the last two armadillo repeats of ß-catenin, which could have consequences for cadherin but not TCF binding. Indeed, alteration of a single residue in the 12th arm repeat of ß-catenin decreases ß-catenin binding to the cadherin by a factor of four (Roura et al., 1999), further arguing that small perturbations in the ß-catenincadherin interface can have significant consequences for binding.
It has also been shown that phosphorylation of E-cadherin increases cadherinß-catenin complex formation (Lickert et al., 2000). In crystal structures, this phosphorylation results in interactions with ß-catenin that appear to mimic TCF binding (Huber and Weis, 2001). Indeed, we find that cadherin phosphorylation allows the cadherin to bind the monomeric, closed form of ß-catenin that otherwise would be TCF selective. The fact that cadherin phosphorylation can reverse Wnt-mediated ß-catenin binding selectivity suggests a mechanism by which cadherins compete for the Wnt-activated form of ß-catenin. It will be important, therefore, to determine when and where cadherin modification occurs to better understand the relationship between adhesion and signaling.
Our observation that the cadherin binds preferentially to ß-catenin-catenin dimers compared with ß-catenin monomers raises the possibility that
-catenin plays a positive role in ß-catenin binding to cadherin. Indeed, one study showed that preassociation of recombinant
-catenin with ß-catenin increases ß-catenin binding to cadherin, suggesting that
-catenin induces an open conformation of ß-catenin (Castano et al., 2002). Other evidence, however, argues that
-catenin is not required for ß-catenin binding to cadherin. For example, recombinant cadherinß-catenin complexes are readily formed in vitro (Huber et al., 2001), and cells lacking
-catenin still form cadherinß-catenin complexes (Bullions et al., 1997; Vasioukhin et al., 2001). We suggest that the form of ß-catenin that binds preferentially to cadherin, also binds
-catenin.
Based on our findings from this and previous reports, we propose that cells contain a number of distinct molecular forms of ß-catenin (Fig. 9). Thus, although an organism like C. elegans controls the adhesive and signaling functions of ß-catenin through expression of a multi-gene family, vertebrates regulate ß-catenin functions by generating distinct molecular forms at the protein level. First, there is the well-known form of ß-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 ß-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 ß-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 ß-catenin that is targeted to transcription complexes (closed conformation), and a form that can target to adhesive complexes (ß-catenin-catenin dimer). Although the latter form can interact with both the cadherin and TCF, there is evidence that
-catenin inhibits the transcriptional activity of ß-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 ß-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 ß-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).
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If we propose that Wnt signaling generates a TCF-selective form of ß-catenin that is resistant to cadherin binding, how do we explain the fact that cadherin expression has been found to antagonize Wnt signaling in numerous model systems (Heasman et al., 1994; Fagotto et al., 1996; Gottardi et al., 2001)? One possibility is that cadherin overexpression of cadherin drives the formation of complexes that do not occur under normal physiological conditions. Although the various molecular forms of ß-catenin seem fairly stable in our experiments, it is possible that they are more interconvertible in the cell, or that one form is an intermediate for the other, and can be depleted during its generation. A more interesting possibility is that the relationship between cadherins and Wnt signaling may depend on the specific situation faced by each cell responding to a Wnt signal. For example, our finding that cadherin phosphorylation increases ß-catenin binding to cadherin, reversing the differential binding activity observed during Wnt signaling, suggests that variations in cadherin phosphorylation may alter the extent to which adhesion and signaling are coupled. We also hypothesize that the cell can potentially generate either the open form of ß-catenin, which binds to both cadherin and TCF, or the closed, TCF-selective form, and the relative proportion of these two forms may differ between different cells responding to Wnt signaling, or different strengths of Wnt signaling.
Indeed, consideration of the various findings suggests a model in which the extent of coupling between the adhesive and nuclear signaling functions of ß-catenin is regulated differentially in different cell types, depending on the biological needs of the cells and tissues responding to a Wnt signal. Elucidating the cellular and biochemical mechanisms regulating the generation of the different forms of ß-catenin and determining when and where they occur should provide insight into the relationship between the adhesive and signaling functions of ß-catenin.
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Materials and methods |
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Antibody and plasmid reagents
Rabbit pAbs to -catenin, and the NH2-terminal region of ß-catenin have been described elsewhere (McCrea et al., 1993); 1:5,000 WB; 1:500 IP). The NH2-terminal and COOH-terminal monoclonal antiß-catenin antibodies (1.1.1 and M5.2, respectively) were provided by N. Gruel, V. Choumet, and J. Luc Teillard (Pasteur Institute, Paris, France). Other antibodies used in this study: antiNH2-terminal dephosphoß-catenin pAb (8E4; A.G. Scientific), antiß-catenin COOH-terminal mAb (C19220; Transduction Laboratories), anti
-catenin mAb (BD Transduction Laboratories), antihuman E-cadherin (HECD-1 mAb; Zymed Laboratories; 1:500 IP), antiTCF-4 (1:500 IP, 6H5-3; Upstate Biotechnology), anti-FLAG epitope (1:5,000 WB, M2 mAb, Sigma-Aldrich) and anti-Myc (1:5,000 WB, 9E10 epitope). The mouse Lin7 GST fusion construct was provided by S. Straight and B. Margolis (University of Michigan, Ann Arbor, MI). Xenopus C-cadherin cytoplasmic domain (cad-GST) and Xenopus TCF-3 ß-catenin binding region (TCF-GST) fusion proteins have been described previously (Gottardi et al., 2001).
Affinity precipitation experiments
Cells were grown to in 14-cm tissue culture dishes and a detergent-free, cytosolic fraction was generated by centrifugation at 100,000 g according to Gottardi et al. (2001). Metabolic labeling of proteins with [35S]methionine/cysteine was done according to Gottardi and Gumbiner (2004). Affinity precipitations were performed with recombinant GST-cad, GST-TCF and GST-mLin7 fusion proteins. For cadherin/TCF-GST binding experiments, 100500 µg of a cytosolic fraction was subjected to affinity precipitation with 40 pmol of cad-GST or TCF-GST prebound as a 50% suspension of glutathione-coupled agarose beads (Sigma-Aldrich) for 60' at 4°C. Each precipitation was washed in a detergent buffer (50 mM Tris, pH 7.5, 2 mM EDTA, 150 mM NaCl and 0.1% NP-40), and bound protein complexes were analyzed by standard Western analysis. For in vitro competition of the ß-cat COOH-terminal peptide (amino acids 696781; provided by A. Garcia de Herreros, Universitat Pompeu Fabra, Barcelona; Castano et al., 2002), the ß-catenin COOH terminus was cleaved from GST with PreScission protease (Amersham Biosciences). ß-Catenin (
17 pmol, produced by the baculovirus system), cadherin-GST (51 pmol), or TCF-GST (51 pmol) were incubated in 150 ml of buffer (10 mM Tris, pH 8.0, 140 mM NaCl, 1 mM EDTA, 0.1% NP-40, 10 µg/ml leupeptin and aprotinin) for 60' at 4°C with shaking in the presence or absence of increasing amounts of the ß-catenin COOH-terminal peptide (0, 0.1, 1.0, 5.0, and 15.0 µg [1.6 nmol peptide]). ß-Catenin that was affinity precipitated by cadherin-GST and TCF-GST immobilized to glutathione-coupled agarose was washed and subjected to SDS-PAGE and Western analysis.
Gel filtration chromatography
The cytosolic fraction was separated on a Hi Prep 16/60 Sephacryl S-300 sizing column (Amersham Biosciences; High Resolution Code 171167-01, 101500 kD inclusion range) equilibrated with buffer containing 30 mM Hepes, pH 7.5, and 150 mM KCl and developed at 0.4 ml/min. 75 2.0-ml fractions were collected.
Online supplemental material
Fig. S1 depicts in vitro phosphorylation of cadherin-GST. (A) Purification of cad-GST and TCF-GST proteins and detection by Coomassie. (B and C) In vitro phosphorylation of cad-GST by CK-2. Cad-GST (3 µg) was incubated with or without 50 U of recombinant human CK-2 (New England Biolabs, Inc.) and 200 or 600 µM ATP using conditions suggested by the manufacturer. Cad-GST input was evaluated with an antibody to GST; evidence for phosphorylation was detected by immunoblotting with an antiP-serine antibody (Sigma-Aldrich). (C) Efficiency of cad-GST phosphorylation: the first and sixth lanes in B were resolved on a long gel to detect the mobility shift of phospho-cad-GST. Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb.200402153/DC1.
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Acknowledgments |
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This work was supported by National Institutes of Health grant R37 GM374432 awarded to B.M. Gumbiner.
Submitted: 26 February 2004
Accepted: 30 August 2004
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