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Galectin-3, a Novel Binding Partner of ß-Catenin

¹ Karmanos Cancer Institute, Wayne State University Medical School, Detroit, Michigan; and ² Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

	ABSTRACT

Top ABSTRACT Introduction Materials and Methods Results and Discussion REFERENCES

 
Galectin-3 (gal-3), a pleiotrophic protein, is an important regulator of tumor metastasis, which like ß-catenin shuttles between the nucleus and the cytosol in a phosphorylation-dependent manner. We report herein that ß-catenin stimulation of cyclin D₁ and c-myc expression is gal-3 dependent. Gal-3 binds to ß-catenin/Tcf complex, colocalizes with ß-catenin in the nucleus, and induces the transcriptional activity of Tcf-4 as determined by the TOP/FOPFLASH reporter system. We have identified the ß-catenin–gal-3–binding sequences, which are in the NH₂ and COOH termini of the proteins encompassing amino acid residues 1 to 131 and 143 to 250, respectively. These data indicate that gal-3 is a novel binding partner for ß-catenin involved in the regulation of Wnt/ß-catenin signaling pathway.

	Introduction

Top ABSTRACT Introduction Materials and Methods Results and Discussion REFERENCES

 
Wnt proteins constitute a large family of cysteine-rich molecules that control development in organisms ranging from nematode worms to mammals (1) . The intracellular signaling pathway of Wnt is evolutionally conserved and regulates cellular proliferation, morphology, motility, axis formation, and organ development (2 , 3) . ß-Catenin is a downstream component of the Wnt signaling pathway. It is phosphorylated by GSK3ß and CKI in a complex that contains APC and axin, targeting ß-catenin for ubiquitination and degradation (4, 5, 6) . In the current model, dephosphorylation of ß-catenin leads to its accumulation and translocation into the nucleus, where it binds to the transcriptional factor Tcf/Lef and serves as a coactivator of Tcf/Lef to stimulate transcription of the Wnt target genes including c-myc and cyclin D₁, among others (7 , 8) . However, the molecular mechanism that targets ß-catenin to the nucleus is still unclear. Galectins are a family of carbohydrate-binding proteins characterized by conserved amino acid sequences defined by structural similarities in their carbohydrate-binding domains and affinity for ß-galactoside–containing glycoconjugates (9) . An important member of this family, e.g., gal-3, has been implicated in diverse biological functions including cell growth, differentiation, apoptosis, adhesion, malignant transformation, and RNA processing (10, 11, 12, 13) . Similarly to ß-catenin, endogenous gal-3 is found in the cytoplasm, on the cell surface, and in the nucleus, where it undergoes post-translational modification by the addition of a phosphate group catalyzed by CK1. Its phosphorylation serves as a signaling switch for nuclear export. In vivo, the nuclear expression of gal-3 is associated with tumor invasion and metastatic potential in various human cancers such as colon, prostate, and tongue squamous carcinoma cells (11 , 14, 15, 16) .

We have previously shown that gal-3 overexpression regulates changes in the expression levels of cell cycle regulators, including cyclin D₁ (13) , and because cyclin D₁ has been reported to be targeted within the Wnt pathway (7) , we questioned the possible association between gal-3 and ß-catenin for molecular shuttling to the nucleus of cancer cells. We propose that gal-3 complex with ß-catenin activate Tcf-reporter activity and stimulate cyclin D₁ and c-myc.

	Materials and Methods

Top ABSTRACT Introduction Materials and Methods Results and Discussion REFERENCES

 
Cells, Antibodies, and Culture Conditions.
The human breast cancer BT549 gal-3 null cell line, its transfectants, and culture conditions are as described were described previously (17) . The colon cancer cell line HT29 contains mutated APC and wild-type ß-catenin, whereas HCT116 contains mutated ß-catenin and wild-type APC; they were purchased from American Type Culture Collection (Manassas, VA). Cells were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mmol/L glutamine, nonessential amino acids, and antibiotics (Invitrogen, Carlsbad, CA). Suspension cultures were performed as described previously (13) . Monoclonal rat anti-gal-3 antibody was purchased (TIB166; American Type Culture Collection). Polyclonal rabbit anti-gal-3 was described elsewhere (10) . Anti-ß-catenin antibody for Western blot and immunofluorescence (BD Biosciences, San Jose, CA), anti-ß-catenin antibody for immunoprecipitation (Upstate, Lake Placid, NY), anti-cyclin D₁ antibody (Sigma, St. Louis, MO), anti-c–myc antibody (Oncogene, San Diego, CA), and anti-Tcf–4 antibodies (Exalpha Biologicals, Watertown, MA).

Plasmid Construction.
pGEX-2T/ß-catenin, pGEX-2T/ß-catenin (1–131), pGEX-2T/ß-catenin (132–423), pGEX-KG/ß-catenin (423–781), pGEX-2T/ß-catenin (1–423), and pGEX-2T/ß-catenin (175–423) were described elsewhere (6) . Production of recombinant glutathione S-transferase (GST)-fusion protein was conducted according to the manufacturer’s recommendation (Amersham Biosciences Corp., Piscataway, NJ). PGEX-6P-2/gal-3 was also described elsewhere. To establish the deletion mutant of gal-3, a Quick Change Site-directed Mutagenesis kit (Stratagene, La Jolla, CA) was used, using pGEX-6P-2/gal-3 as a template. To construct Gal-3 deletion mutant 1–62, 1–93, and 1–142, tyrosine⁶³, glycin⁹⁴, and asparagine¹⁴³ were substituted to the stop codon, TAG, using specific primers as follows: sense for 1–62, 5'-CAGGCACCTCCAGGCGCCTAGCATGGAGCACCTGGAGCTTATCCC-3'; antisense, 5'-GGGATAAGCTCCAGGTGCTCCATGCTAGGCGCCTGGAGGTGCCTG-3'; sense for 1–93, 5'-GGGGCCTACCCATCTTCTGGATAGCCAAGTGCCCCCGGAGCCTAC-3'; antisense, 5'-GTAGGCTCCGGGGGCACTTGGCTATCCAGAAGATGGGTAGGCCCC-3'; sense for 1–142, 5'-GAGTCATTGTTTGCAATACATAGCTGGATAATAACTGGGGAAGGG-3'; and antisense, 5'-CCCTTCCCCAGTTATTATCCAGCTATGTATTGCAAACAATGACTC-3'. To check accuracy of site-directed mutation, produced plasmids were sequenced at Wayne State University DNA Sequencing Core (Detroit, MI). pGEX-6P-2/gal-3 (62–250) was constructed by an insertion of an EcoRI-EcoRI fragment coding cleaved human gal-3 sequence into the EcoRI site in the pGEX-6p-2. To generate cleaved gal-3 fragment coding the COOH-terminal domain (NH₂-terminal 62 amino acids deleted) of human gal-3, a sense primer (5'-CAGAATTCTGTTATGTACCATGGAGCACCTG-3') and an antisense primer (5'-CCTGAATTCAGATTATATCATGGTATATGAAGC-3') containing a flanking EcoRI cleavage site were synthesized using plasmid pBK-CMV-Gal-3 as a template. A PCR product was purified and inserted into EcoRI-digested vector pGEX-6p-2 [designated as pGEX-6P-2/Gal-3 (63–250)].

Immunoprecipitation.
To determine whether gal-3 forms a complex with ß-catenin, immunoprecipitation was performed. Cell supernatants were immunoprecipitated with anti-gal-3, anti-ß-catenin, or anti-Tcf–4 antibody for 60 minutes at 4°C. Then 30 µL of 1:2 slurry of protein G-Sepharose were added for 60 minutes at 4°C. After centrifugation, the precipitate was mixed with 20 µL of SDS-PAGE sample buffer and boiled. In all immunoprecipitation, we confirmed that no coimmunoprecipitants were detected when precipitated with control normal serum.

Luciferase Assay.
To examine whether galectin overexpression augments transcriptional activity of the Tcf-reporter plasmid, BT549 parental cells were transiently transfected with pcDNA3.1+/Zeo/gal-3 (1 µg), cotransfected with 0.5 µg of pTOPFLASH or pFOPFLASH (Upstate). Forty-eight hours after transfection, the cells were collected and cultivated on poly-HEMA–coated dishes for the indicated time. After lysis with reporter lysis buffer, luciferase activity was measured using a Luciferase Assay System (Promega, Madison, WI) and luminophotometer TD-20/20 (Turner Designs, Sunnyvale, CA). To observe whether transiently transfected gal-3 also augments Tcf-reporter activity in HT29, pcDNA3.1+/Zeo/gal-3 was transiently transfected into HT29 cells and cotransfected with pTOPFLASH or pFOPFLASH (0.5 µg). After 48 hours, the cells were lysed, and activity was measured using a Luciferase Assay System and luminophotometer TD-20/20. The results were calculated as pTOPFLASH to pFOPFLASH ratio.

Mapping the Binding Region between ß-Catenin and Galectin-3.
For determination of the region of ß-catenin that binds to gal-3, various deletion mutants of GST–ß-catenin (each at 250 nmol/L) were incubated with 250 nmol/L gal-3 (full length) for 1 hour at 4°C in 50 µL of reaction mixture [20 mmol/L Tris-HCl (pH 7.5) and 1 mmol/L dithiothreitol). GST–ß-catenin deletion mutants were precipitated with glutathione-Sepharose 4B and probed with anti-gal-3 antibody. Reciprocally, deletion mutants of gal-3 protein (250 nmol/L) were incubated with 250 nmol/L ß-catenin for 1 hour at 4°C in 50 µL of reaction mixture. The mixture was precipitated with anti-ß-catenin antibody and probed with anti-gal-3 antibodies.

	Results and Discussion

Top ABSTRACT Introduction Materials and Methods Results and Discussion REFERENCES

 
ß-Catenin–Galectin-3 Interaction.
Previously, it was reported that gal-3 induces cyclin D1 promoter activity and up-regulates cyclin D₁ expression in suspension culture. It was suggested that this regulation is through enhancement/stabilization of cAMP-responsive element-associated complex (13) . These findings prompted us to examine a possible link between Wnt pathway and gal-3, because both cyclin D₁ and c-myc are targets of this pathway. Thus, we have activated gal-3 by anoikis and found an induction of transcriptional activity of ß-catenin–dependent genes, e.g., cyclin D₁ and c-myc only in cells expressing gal-3 (Fig. 1, II) . To explore whether gal-3 forms a complex with ß-catenin, the lysates of BT549-Gal cells from monolayer clusters were immunoprecipitated with either anti-gal-3 or anti-ß-catenin antibodies and reciprocally blotted with anti-ß-catenin or anti-gal-3 antibodies. When the lysates of the cells were pulled down with antibody directed against gal-3, separated by electrophoresis, and Western analyzed with anti-ß-catenin antibody, ß-catenin associated with gal-3 was detected (Fig. 2A) . In reciprocal experiments, whereby the lysates were immunoprecipitated with anti-ß-catenin antibody and Western blot analysis was done with anti-gal-3 antibody, gal-3–associated ß-catenin was detected (Fig. 2B) . Next, we questioned whether the gal-3–ß-catenin interaction is carbohydrate dependent. To this end, we tested lactose, a specific gal-3 inhibitor. Formation of the complex between ß-catenin and gal-3 was inhibited by low (50 mmol/L) lactose concentration present in the lysis buffer; specificity of the inhibition was confirmed by using 50 mmol/L sucrose as a control (Fig. 2C) . It should be noted that ß-catenin is not a glycoprotein, suggesting that specific sugar inhibition could have resulted from a conformational change of gal-3 due to occupancy of the sugar-binding site. These findings are supported by the observation that a naturally occurring complex carbohydrate rich in galactose, i.e., pectin, inhibits ß-catenin expression in the colon (18) . This might explain the inhibitory effect of modified pectin on the growth and metastasis of human breast carcinoma in nude mice (19) , possibly due to inhibition of gal-3–ß-catenin complex formation.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Expression of cyclin D1 and c-myc in human breast carcinoma BT549 cells. I, control, BT549-vCTR cell clone (gal3–3 null); II, BT549-Gal cell clone. Cells harvested from semiconfluent cultures were plated onto poly-HEMA-coated dishes for 0, 2, 4, and 6 hours. After culturing, cells were lysed and Western analyzed with anti-cyclin D1 or anti-c-myc antibodies. Antiactin antibody was used for control protein loading. These are the representative data from three sets of experiments.

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. ß-Catenin–gal-3 interaction. A, Cell lysates of BT549-Gal were immunoprecipitated with anti-ß-catenin antibody and probed with anti-ß-catenin antibodies (Lane ß-catenin); the same lysates were immunoprecipitated with anti-gal-3 and probed with anti-ß-catenin (Lane galectin-3). B, The same cell lysates were precipitated with rabbit polyclonal anti-gal-3 and probed with monoclonal anti-gal-3 antibodies (Lane galectin-3) or immunoprecipitated with anti-ß-catenin antibodies and probed with monoclonal anti-gal-3 (Lane ß-catenin). C, When the cell lysates of were prepared with 50 mmol/L lactose (+ lactose), gal-3 was not coprecipitated with ß-catenin, whereas when the lysates prepared with 50 mmol/L of sucrose, coprecipitation was detected (+ sucrose), similar to the control of no sugar (– lactose, – sucrose, top and B). D, BT549-vCTR (a and b) and BT549-Gal (d and e) cells were cultivated on glass coverslips for 48 hours, washed with PBS, fixed, and immunostained. Immunofluorescent analysis was performed with anti-gal-3 antibodies (a–c) and anti-ß-catenin antibodies (e and f). ß-Catenin is shown in green and gal-3 in red. The merged images of a and b are depicted in c, and that of d and e are depicted in f. Colocalization is revealed by change of colors to orange-yellow.

Tcf-4 and Galectin-3 Interaction.
Based on the data presented above, we questioned (1) whether the ß-catenin–gal-3 complex also contains Tcf-4 protein and (2) whether ß-catenin–gal-3 complex formation is affected by either APC or ß-catenin amino acid mutations. To address these, we examined two human colon cancer cell lines: (1) the HT29 cell line, which contains mutated APC and wild-type ß-catenin proteins, and (2) the HCT116 cell line, which harbors ß-catenin mutation and wild-type APC proteins. Pull-down immunoprecipitations followed by Western analyses revealed that both ß-catenin and gal-3 complex could be detected in the cell lysates of both cell lines (Fig. 3) . ß-Catenin was pulled down by antigalectin antibodies (Fig. 3, I , Lanes 1 and 2), and gal-3 was pulled down by anti-ß-catenin antibodies (Fig. 3, I , Lanes 3 and 4). Gal-3 pulled-down Tcf-4 (Fig. 3, I , Lane 5) and reciprocally was pulled down by anti-Tcf-4 antibodies (Fig. 3, I , Lane 6). Thus, we report that gal-3 forms a complex with ß-catenin independent of either APC or ß-catenin mutations or that in the cells tested here, gal-3 forms a ternary complex with ß-catenin and Tcf-4.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. I, Interaction of gal-3 with ß-catenin and Tcf-4. Cell lysates of HT29 (Lanes 1 and 3) and HCT116 (Lanes 2 and 4) were precipitated with anti-gal-3 antibodies and either probed with anti-ß-catenin antibodies (Lanes 1 and 2) or precipitated with anti-ß-catenin and probed with anti-gal-3 antibodies (Lanes 3 and 4). Controls (bottom) depict the amounts of ß-catenin and gal-3 immunoprecipitated from each fraction by the respective antibodies and reblotting with the same antibodies. The cell lysates of HT29 were immunoprecipitated with anti-gal-3 antibodies and probed with anti-Tcf-4 antibodies (Lane 5) or, reciprocally, precipitated with anti-Tcf-4 antibody and probed with anti-gal-3 (Lane 6). Controls (bottom) depict the amounts of Tcf-4 and gal-3 immunoprecipitated from each fraction by the respective antibodies. II, Tcf-reporter assay. A, BT549 wild-type cells were transiently transfected with 1 µg of pcDNA3.1+/Zeo/gal-3 () or mock vector () and cotransfected with pTOPFLASH or pFOPFLASH. The cells were harvested after 48 hours in culture and subjected to suspension culture on poly-HEME-coated dishes for 0, 2, 4, and 6 hours. Each value is the mean of the acquired results calculated by pTOPFLASH/pFOPFLASH ratio. There was a statistical significance between two groups (P < 0.05) by unpaired t test. These are the representative data of three independent sets of experiments. B, HT29 cells were transiently transfected with mock vector (vector) or the indicated amount of pcDNA3.1+/Zeo/gal-3. Each data point represents the pTOPFLASH/pFOPFLASH ratio.

ß-Catenin– and Galectin-3–Binding Domains.
Next, we attempted to determine the target motifs in ß-catenin and gal-3 sequences that are required for their molecular interaction. We performed in vitro pull-down assays with GST proteins and peptides. We have generated various deletion mutant proteins of ß-catenin (Fig. 4A) and gal-3 (Fig. 4B) , spanning the entire sequence. The proteins were expressed and purified as GST fusion proteins. The GST–fusion-ß-catenin mutant proteins were incubated with full-length gal-3 protein and precipitated thereafter with glutathione-Sepharose. As shown in Fig. 4C , gal-3 was coprecipitated with GST–ß-catenin (full length), GST–ß-catenin (1–423) and (1–131) peptides, but not with either GST–ß-catenin (132–423) and GST–ß-catenin (175–423) or GST–ß-catenin (423–781) peptides. Reciprocally, to determine the motif of gal-3 that binds to ß-catenin, full-length ß-catenin protein and deleted peptides were incubated with gal-3 and immunoprecipitated thereafter (Fig. 4D) . ß-Catenin was coprecipitated with intact recombinant gal-3 (full length) and gal-3 (63–250)-deleted peptide but not with gal-3 (1–62), gal-3 (1–92), or gal-3 (1–142) peptides. Thus, we concluded that the NH₂ terminus of ß-catenin interacts with the COOH terminus of gal-3 encompassing amino acid residues 1–131 and 63–250, respectively. Of note, this structural domain contains the ß-galactoside–binding motif of gal-3 and thus might explain the observed inhibitory effect of lactose on ß-catenin–gal-3 complex formation (Fig. 2C) . The ß-catenin region (1–131 amino acids), which is also involved in its interaction with -catenin and is prerequisite for oncogenicity (20) , might suggest that a competition between gal-3 and -catenin for ß-catenin binding leads to its the displacement from the membrane.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Binding region between ß-catenin and gal-3. Depiction of the generation scheme of the deletion mutant of ß-catenin (A) and of gal-3 (B) GST fusion proteins of the deletion mutant of ß-catenin. GST fusion proteins were prepared according to the manufacturer’s instruction and subjected to SDS-PAGE, followed by Coomassie Brilliant Blue staining. Purified deletion mutants of gal-3 were subjected to SDS-PAGE, followed by Coomassie Brilliant Blue staining. Binding assay between gal-3 and the deletion mutant of ß-catenin. C, The GST–ß-catenins (each at 250 nmol/L) were incubated with 250 nmol/L gal-3 peptides for 1 hour at 4°C in 50 µL of reaction mixture, as described in Materials and Methods. D, The gal-3 peptides were incubated with ß-catenin (full length) in the reaction mixture. The mixture was precipitated with anti-ß-catenin and probed with anti-gal-3 antibodies.

	ACKNOWLEDGMENTS

 
We thank Drs. J. Horwitz, S. Ratner, and G. S. Wu for reviewing the manuscript and V. Powell for editing.

	FOOTNOTES

 
Grant support: NIH/National Cancer Institute grant CA46120 (A. Raz).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Notes: T. Shimura and S. Tsutsumi are currently at the Department of General Surgical Science, Graduate School of Medical Sciences, Gunma University, Gunma, Japan.

Requests for reprints: Avraham Raz, Karmanos Cancer Institute, Wayne State University Medical School, 110 East Warren Avenue, Detroit, MI 48201. Phone: 313-833-0960; Fax: 313-831-7518; E-mail: raza{at}karmanos.org

Received 5/24/04. Revised 7/ 6/04. Accepted 8/ 3/04.

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