Entry - *153619 - LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 3; LGALS3 - OMIM
 
* 153619

LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 3; LGALS3


Alternative titles; symbols

MACROPHAGE GALACTOSE-SPECIFIC LECTIN; MAC2
GALACTOSIDE-BINDING PROTEIN; GALBP
GALECTIN 3; GAL3


Other entities represented in this entry:

GALECTIN 3 INTERNAL GENE, INCLUDED; GALIG, INCLUDED

HGNC Approved Gene Symbol: LGALS3

Cytogenetic location: 14q22.3   Genomic coordinates (GRCh38) : 14:55,129,252-55,145,430 (from NCBI)


TEXT

Cloning and Expression

The murine Mac2 protein is a galactose- and IgE-binding lectin secreted by inflammatory macrophages. Cherayil et al. (1990) cloned and characterized a cDNA representing the human homolog. The amino acid sequence derived therefrom indicated that the protein is evolutionarily highly conserved, especially in the C-terminal lectin domain. Human MAC2 synthesized in vitro is recognized by a monoclonal antibody to mouse Mac2 and behaves like a galactose-specific lectin in its binding to the desialylated glycoprotein asialofetuin. It also binds to purified laminin (see 150320), indicating a potential role in macrophage extracellular matrix interactions. MAC2 is also known as galectin-3 (LGALS3), as mentioned in Madsen et al. (1995).

From a human fibrosarcoma cDNA library, Raz et al. (1991) cloned a galactoside-binding protein with a molecular weight of 31,000. The deduced 242-amino acid protein has the characteristics of a carbohydrate-binding protein. The deduced amino acid sequence contains 95 residues at the N terminus that are homologous to the predicted amino acid sequence of the second exon of the oncogene LMYC (164850).

Huflejt et al. (1997) found that LGALS3 and LGALS4 (602518) have very different cellular localizations in human colon adenocarcinoma T84 cells, suggesting that these LGALSs have different targeting mechanisms, ligands, and functions. In confluent T84 cells, LGALS3 is concentrated mainly at the apical membrane in large granular inclusions. In subconfluent T84 cells, it is distributed along most of the cell periphery and is concentrated in the posterior part of lamellipodia.

By RT-PCR of a human osteosarcoma cell line, Raimond et al. (1995) identified galectin-3 transcripts initiated from the promoter upstream of exon 1 and from the internal promoter within intron 2. Using RT-PCR and EST database analysis, Guittaut et al. (2001) obtained transcripts originating from the internal promoter in intron 2 of LGALS3 from several cDNA libraries. They concluded that these transcripts arise from a gene embedded within LGALS3 that they called 'galectin-3 internal gene,' or GALIG. The GALIG transcripts contain 2 overlapping ORFs, ORF1 and ORF2, that initiate in exon 3 of LGALS3 and are out-of-frame relative to the LGALS3 coding sequence. RT-PCR detected variable and tissue-specific expression of LGALS3 and GALIG transcripts. GALIG transcripts showed highest expression in peripheral blood leukocytes, but overall they were much less abundant than LGALS3 transcripts. In transfected osteosarcoma cells, fluorescence-tagged ORF1 localized to cytosol and nucleus, and fluorescence-tagged ORF2 localized to mitochondria.


Gene Function

Galectin-3 is expressed in various tissues and organs, but is significantly absent in normal hepatocytes. However, evaluation of patient liver biopsies for galectin-3 expression revealed that hepatocellular carcinoma (HCC) frequently expressed significant levels of this lectin; 76% were immunohistochemically positive. Further investigations showed that galectin-3 expression in HCC is independent of whether the patient had prior hepatitis B virus infection (Hsu et al., 1999). Hsu et al. (1999) suggested that deregulated expression of galectin-3 can result in tumor transformation and invasiveness, or confer propensity for tumor cell survival.

Using reporter gene assays, Raimond et al. (1995) showed that p53 (TP53; 191170) downregulated expression of the GALIG promoter when cotransfected into a human osteosarcoma cell line.

In the thyroid, expression of galectin-3 protein had been described in differentiated follicular cancer, suggesting that the immunohistochemical study of galectin-3 may be a potential marker of malignancy in thyroid neoplasms. Martins et al. (2002) analyzed galectin-3 protein and mRNA expression in thyroid tissues from 87 patients with histomorphologic diagnosis of multinodular goiter (MNG), follicular adenoma, follicular carcinoma, papillary carcinoma, and 5 normal tissues. Galectin-3 mRNA expression was detected by RT-PCR. Their results showed that the majority of carcinomas expressed galectin-3 protein (follicular, 90%; papillary, 100%). However, in contrast to the previously published data, benign lesions also expressed galectin-3 (adenoma, 45%; MNG, 17%). The authors showed by RT-PCR that thyroid tissues with diagnosis of adenoma and MNG expressed galectin-3 mRNA. Although the galectin-3 immunostaining demonstrated a sensitivity of 93.8% in the identification of cancer, the accuracy in the distinction between benign and malignant tissues was 77.0%. This accuracy was even lower (68.6%) when galectin-3 expression in follicular adenoma was compared with follicular carcinoma.

Using micro-Boyden chamber analysis, Sano et al. (2000) determined that LGALS3 has chemoattractant activity not for eosinophils, like LGALS9 (601879), but for monocytes and mature macrophages. At high concentrations LGALS3 activity is chemotactic, i.e., cells migrate towards the attractant, whereas at low concentrations it is chemokinetic, i.e., it enhances movement of cells in all directions. Sano et al. (2000) found that the chemoattractant activity is inhibited by lactose, indicating that the C-terminal lectin domain of LGALS3 is required. A C-terminal domain fragment was unable to mediate chemoattraction, suggesting that the N-terminal domain is also necessary for activity. Both migration and increased intracellular calcium concentration were pertussis toxin sensitive and therefore probably mediated by a G protein-coupled receptor. The authors determined that LGALS3 does not, however, use the chemokine receptors CCR1 (601159), CCR2 (601267), CCR5 (601373), and CXCR4 (162643).

Yoshimura et al. (2003) found increased expression of the LGALS3 gene in human nonsmall cell lung cancer, and suggested that it may play a role in the process of metastasis in this malignancy but not in small cell lung cancer. They considered that LGALS3 may be a phenotypic marker that excludes small cell lung cancer and a novel target molecule in therapy of nonsmall cell lung cancer.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (HRAS, 190020; NRAS, 164790; KRAS, 190070) mutations and PAX8 (167415)-PPARG (601487) rearrangements using molecular methods and for galectin-3 and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.

Ohshima et al. (2003) found that galectin-3 mRNA and protein are expressed throughout synovial tissue in rheumatoid arthritis (RA; 180300) and that both galectin-3 and its binding protein are found at sites of joint destruction. In addition, levels of galectin-3 in serum and synovial fluid as well as levels of its binding protein in synovial fluid were significantly elevated in RA compared to osteoarthritis and healthy controls (p less than 0.001). Serum galectin-3 levels correlated significantly with C-reactive protein levels (p less than 0.001), and levels of its binding protein correlated with levels of cartilage oligomeric matrix protein in both serum and synovial fluid (p less than 0.001 and 0.005, respectively). In vitro, RA synovial fibroblasts showed an increased release of galectin-3 into culture medium but decreased secretion of its binding protein. Ohshima et al. (2003) concluded that galectin-3 and its binding protein are not only involved in inflammation but also contribute to the activation of synovial fibroblasts, and thus represent markers of disease activity in rheumatoid arthritis.

Partridge et al. (2004) reported that expression of Mgat5 (601774) sensitized mouse cells to multiple cytokines. Gal3 crosslinked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor-beta receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5 expression in mammary carcinoma was rate limiting for cytokine signaling and consequently for epithelial-mesenchymal transition, cell motility, and tumor metastasis. Mgat5 also promoted cytokine-mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Partridge et al. (2004) concluded that conditional regulation of N-glycan processing drives synchronous modification of cytokine receptors, which balances their surface retention against loss through endocytosis.

Henderson et al. (2006) found that galectin-3 was upregulated in established human fibrotic liver disease. In experimental hepatic fibrosis in rats, galectin-3 upregulation was associated with induction and resolution of fibrosis. Disruption of the galectin-3 gene blocked myofibroblast activation and procollagen I expression in vitro and in vivo and attenuated liver fibrosis. Exogenous recombinant galectin-3 reversed this abnormality. Following liver injury and inflammation, hepatic fibrosis was reduced in galectin-3-null mice compared with wildtype mice. Tgf-beta (190180) failed to activate galectin-3-null mouse hepatic stellate cells, indicating that galectin-3 is required for Tgf-beta-mediated myofibroblast activation and matrix production.

Both MUC1 (158340) and galectin-3 are widely expressed in human carcinomas. Ramasamy et al. (2007) showed that, following glycosylation on asn36, the MUC1 C-terminal subunit (MUC1C) induced galectin-3 expression by suppressing expression of miRNA322 (MIRN322; 300682), a microRNA that destabilizes galectin-3 transcripts. In turn, galectin-3 bound MUC1C at the glycosylated asn36 site and formed a bridge between MUC1 and epidermal growth factor receptor (EGFR; 131550), integrating MUC1 with EGF (131530) signaling.

Mazurek et al. (2007) stated that GAL3 may exert anti- or pro- apoptotic activity depending on the cell type and the nature of the stimulus. They showed that introduction of phosphorylated GAL3 into a GAL3-null human breast cancer cell line promoted apoptotic cell death through TRAIL (TNFSF10; 603598), a member of the tumor necrosis factor family that transmits death signals through death domain-containing receptors. Downstream, TRAIL sensitivity depended upon induction of PTEN (601728) expression, resulting in inactivation of the PI3K (see PIK3CA; 171834)/AKT (AKT1; 164730) survival pathway.

Chen et al. (2009) reported that Cd4 (186940)-positive T cells from mice lacking Gal3 secreted more Ifng (147570) and Il4 (147780) than wildtype cells after engagement of the T-cell receptor (TCR). In activated mouse and human T cells, GAL3 was recruited to the cytoplasmic side of the immunologic synapse, primarily in the peripheral supramolecular activation cluster (SMAC). Wildtype mouse T cells formed central SMAC less effectively and adhered to antigen-presenting cells less firmly than Gal3 -/- cells, suggesting that GAL3 is involved in stabilizing the immunologic synapse. Yeast 2-hybrid analysis of a human T-cell cDNA library, followed by coimmunoprecipitation and immunofluorescence analyses, identified ALIX (PDCD6IP; 608074) as a GAL3 binding partner and showed that ALIX translocated to the immunologic synapse in activated T cells. Chen et al. (2009) concluded that GAL3 is an inhibitory regulator of T-cell activation and that it functions intracellularly by promoting TCR downregulation, possibly through modulation of ALIX function at the immunologic synapse.

Using real-time quantitative PCR, Mammen et al. (2017) found significantly increased Gal3, Il17 (see 603149), and Tgf-beta-1 gene expression in lung tissue of ovalbumin (OVA)-sensitized Timp1 (305370)-knockout mice, a model of allergic asthma, compared with sham-treated wildtype mice. ELISA revealed significantly increased Gal3 protein levels in serum of OVA-sensitized wildtype and Timp1-knockout mice compared with sham-treated wildtype and Timp1-knockout mice, but the increase was higher in the Timp1-knockout mice. Real-time quantitative PCR and Western blot analyses demonstrated increased Gal3 gene and protein expression in lung tissue of OVA-sensitized wildtype and Timp1-knockout mice compared with sham-treated wildtype and Timp1-knockout mice. Knockdown of GAL3 expression in A549 human lung epithelial cells suggested that GAL3 plays a pivotal role in the balance between a proinflammatory response and a protective antiinflammatory response by modulating IL17 levels.

Zhou et al. (2018) found that expression and accumulation of Gal3 increased in lungs during bleomycin-induced fibroproliferative repair in Hps1 (203300)-deficient 'pale ear' mice, a model of Hermansky-Pudlak syndrome-1 (HPS1; 203300), compared with wildtype mice. Fibroblasts and macrophages from pale ear mice expressed and contained more Gal3 than wildtype cells and had a Gal3 trafficking defect that augmented intracellular accumulation of Gal3 and decreased secretion of Gal3 into extracellular space. In contrast, lung epithelial cells did not show induction or production of Gal3 in wildtype or pale ear mice. Comparison of the bleomycin-induced epithelial injury (apoptosis) and fibroproliferative repair (collagen accumulation) responses showed that intracellular Gal3 drove fibroproliferative repair by inhibiting fibroblast apoptosis, increasing fibroblast proliferation and differentiation. Extracellular Gal3, on the other hand, was a potent stimulator of lung epithelial apoptosis and did not produce effects like those of intracellular Gal3. Intracellular Gal3 did not regulate macrophage apoptosis but increased M2-like macrophage differentiation in pale ear mice. Further analysis showed that Gal3 inhibited the antiapoptotic effects of Chi3l1 (601525) to activate antiapoptotic signaling pathways and played a critical role in Chi3l1-induced Wnt (see 606359)/beta-catenin (CTNNB1; 116806) signaling in lung macrophages. Coimmunoprecipitation analysis demonstrated that Gal3 physically interacted with Chi3l1 and its receptor components, thereby abrogating Chi3l1-induced antiapoptotic signaling, augmenting Wnt/beta-catenin signaling, and contributing to development of epithelial cell death and tissue fibrosis in lungs of Hps1-deficient mice.

Using mice and mouse and human cells, Chen et al. (2019) showed that secretion of galectin-3, including serum galectin-3, relied on activation of the NLRP3 (606416) inflammasome. The exosome pathway did not mediate NLRP3 inflammasome-driven galectin-3 secretion. Instead, gasdermin D (GSDMD; 617042) perforated the plasma membrane to allow nonexosomal release of galectin-3. Knockout analysis in mice demonstrated that galectin-3 was an Nlrp3 inflammasome effector that desensitized insulin signaling. Nlrp3 inflammasome-mediated galectin-3 secretion exacerbated insulin resistance in mice.


Gene Structure

Guittaut et al. (2001) reported that the LGALS3 gene contains 6 exons. It has a proximal promoter upstream of exon 1 and a conserved internal promoter within the 5-prime region of intron 2.


Mapping

Raz et al. (1991) mapped the gene encoding galactoside-binding protein, symbolized GALBP by them, to 1p13 by in situ hybridization. Conflicting mapping results were obtained by Raimond et al. (1997), who mapped the LGALS3 gene to 14q21-q22 by fluorescence in situ hybridization and confirmed the location by isotopic hybridization with a tritium-labeled probe. No secondary peak of hybridization was observed by either method on the short arm of chromosome 1 where the gene had been tentatively assigned by Raz et al. (1991). Presumably, the chromosome 14 location is the true one.


Animal Model

Neutrophil extravasation is mediated by ITGB2 (600065) and selectins (e.g., SELE; 131210). Using an in vivo streptococcal pneumonia mouse model, Sato et al. (2002) showed by Western blot analysis an accumulation of galectin-3 in the bronchoalveolar lavage fluid that correlated with the kinetics of neutrophil emigration to alveoli during S. pneumoniae, but not E. coli, infection. Immunohistochemical analysis demonstrated galectin-3 expression on endothelial and epithelial cell layers and interstitial spaces in lung tissue. Functional analysis indicated that galectin-3 promoted neutrophil adhesion to endothelial cells and that this resulted from direct crosslinking of neutrophils and was dependent on galectin-3 oligomerization. Sato et al. (2002) suggested that galectin-3 plays a role in ITGB2-independent neutrophil extravasation during alveolar infection with S. pneumoniae.

Using models of corneal wound healing, Cao et al. (2002) found that reepithelialization of wounds was significantly slower in Gal3-null mice compared with wildtype mice, and the difference was not due to a reduced epithelial cell proliferation rate. Gene expression analysis using cDNA microarrays revealed that healing corneas of Gal3-null mice had reduced levels of Gal7 (600615). Exogenous application of Gal7, but not Gal3, accelerated reepithelialization of wounds in Gal3-null mice. Both Gal3 and Gal7 accelerated corneal wound healing in wildtype mice. Cao et al. (2002) concluded that both GAL3 and GAL7 play a role in reepithelialization of corneal wounds.

Sano et al. (2003) demonstrated reduced phagocytosis of IgG-opsonized erythrocytes and apoptotic thymocytes in Gal3 -/- macrophages compared to wildtype. Gal3-null mice showed attenuated phagocytic clearance of apoptotic thymocytes by peritoneal macrophages and reduced IgG-mediated phagocytosis of erythrocytes by Kupffer cells in a mouse model of autoimmune hemolytic anemia. Extracellular Gal3 did not contribute to phagocytosis. Sano et al. (2003) concluded that GAL3 may play an important role in both innate and adaptive immunity by contributing to phagocytic clearance of microorganisms and apoptotic cells.


REFERENCES

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  2. Chen, H.-Y., Fermin, A., Vardhana, S., Weng, I.-C., Lo, K. F. R., Chang, E.-Y., Maverakis, E., Yang, R.-Y., Hsu, D. K., Dustin, M. L., Liu, F.-T. Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc. Nat. Acad. Sci. 106: 14496-14501, 2009. [PubMed: 19706535, images, related citations] [Full Text]

  3. Chen, Y., Wang, H., Shen, J., Deng, R., Yao, X., Guo, Q., Lu, A., Sun, B., Zhang, Y., Meng, G. Gasdermin D drives the nonexosomal secretion of galectin-3, an insulin signal antagonist. J. Immun. 203: 2712-2723, 2019. [PubMed: 31597705, related citations] [Full Text]

  4. Cherayil, B. J., Chaitovitz, S., Wong, C., Pillai, S. Molecular cloning of a human macrophage lectin specific for galactose. Proc. Nat. Acad. Sci. 87: 7324-7328, 1990. [PubMed: 2402511, related citations] [Full Text]

  5. Guittaut, M., Charpentier, S., Normand, T., Dubois, M., Raimond, J., Legrand, A. Identification of an internal gene to the human galectin-3 gene with two different overlapping reading frames that do not encode galectin-3. J. Biol. Chem. 276: 2652-2657, 2001. [PubMed: 11160123, related citations] [Full Text]

  6. Henderson, N. C., Mackinnon, A. C., Farnworth, S. L., Poirier, F., Russo, F. P., Iredale, J. P., Haslett, C., Simpson, K. J., Sethi, T. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc. Nat. Acad. Sci. 103: 5060-5065, 2006. [PubMed: 16549783, images, related citations] [Full Text]

  7. Hsu, D. K., Dowling, C. A., Jeng, K.-C. G., Chen, J.-T., Yang, R.-Y., Liu, F.-T. Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma. Int. J. Cancer 81: 519-526, 1999. [PubMed: 10225438, related citations] [Full Text]

  8. Huflejt, M. E., Jordan, E. T., Gitt, M. A., Barondes, S. H., Leffler, H. Strikingly different localization of galectin-3 and galectin-4 in human colon adenocarcinoma T84 cells: galectin-4 is localized at sites of cell adhesion. J. Biol. Chem. 272: 14294-14303, 1997. [PubMed: 9162064, related citations] [Full Text]

  9. Madsen, P., Rasmussen, H. H., Flint, T., Gromov, P., Kruse, T. A., Honore, B., Vorum, H., Celis, J. E. Cloning, expression, and chromosome mapping of human galectin-7. J. Biol. Chem. 270: 5823-5829, 1995. [PubMed: 7534301, related citations] [Full Text]

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  11. Martins, L., Matsuo, S. E., Ebina, K. N., Kulcsar, M. A. V., Friguglietti, C. U. M., Kimura, E. T. Galectin-3 messenger ribonucleic acid and protein are expressed in benign thyroid tumors. J. Clin. Endocr. Metab. 87: 4806-4810, 2002. [PubMed: 12364477, related citations] [Full Text]

  12. Mazurek, N., Sun, Y. J., Liu, K.-F., Gilcrease, M. Z., Schober, W., Nangia-Makker, P., Raz, A., Bresalier, R. S. Phosphorylated galectin-3 mediates tumor necrosis factor-related apoptosis-inducing ligand signaling by regulating phosphatase and tensin homologue deleted on chromosome 10 in human breast carcinoma cells. J. Biol. Chem. 282: 21337-21348, 2007. [PubMed: 17420249, related citations] [Full Text]

  13. Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., II, Tallini, G., Kroll, T. G., Nikiforov, Y. E. RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocr. Metab. 88: 2318-2326, 2003. [PubMed: 12727991, related citations] [Full Text]

  14. Ohshima, S., Kuchen, S., Seemayer, C. A., Kyburz, D., Hirt, A., Klinzing, S., Michel, B. A., Gay, R. E., Liu, F.-T., Gay, S., Neidhart, M. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum. 48: 2788-2795, 2003. [PubMed: 14558084, related citations] [Full Text]

  15. Partridge, E. A., Le Roy, C., Di Guglielmo, G. M., Pawling, J., Cheung, P., Granovsky, M., Nabi, I. R., Wrana, J. L., Dennis, J. W. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306: 120-124, 2004. [PubMed: 15459394, related citations] [Full Text]

  16. Raimond, J., Rouleux, F., Monsigny, M., Legrand, A. The second intron of the human galectin-3 gene has a strong promoter activity down-regulated by p53. FEBS Lett. 363: 165-169, 1995. [PubMed: 7729540, related citations] [Full Text]

  17. Raimond, J., Zimonjic, D. B., Mignon, C., Mattei, M.-G., Popescu, N. C., Monsigny, M., Legrand, A. Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21-22. Mammalian Genome 8: 706-707, 1997. [PubMed: 9271684, related citations] [Full Text]

  18. Ramasamy, S., Duraisamy, S., Barbashov, S., Kawano, T., Kharbanda, S., Kufe, D. The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Molec. Cell 27: 992-1004, 2007. [PubMed: 17889671, images, related citations] [Full Text]

  19. Raz, A., Carmi, P., Raz, T., Hogan, V., Mohamed, A., Wolman, S. R. Molecular cloning and chromosomal mapping of a human galactoside-binding protein. Cancer Res. 51: 2173-2178, 1991. [PubMed: 2009535, related citations]

  20. Sano, H., Hsu, D. K., Apgar, J. R., Yu, L., Sharma, B. B., Kuwabara, I., Izui, S., Liu, F.-T. Critical role of galectin-3 in phagocytosis by macrophages. J. Clin. Invest. 112: 389-397, 2003. [PubMed: 12897206, images, related citations] [Full Text]

  21. Sano, H., Hsu, D. K., Yu, L., Apgar, J. R., Kuwabara, I., Yamanaka, T., Hirashima, M., Liu, F.-T. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J. Immun. 165: 2156-2164, 2000. [PubMed: 10925302, related citations] [Full Text]

  22. Sato, S., Ouellet, N., Pelletier, I., Simard, M., Rancourt, A., Bergeron, M. G. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J. Immun. 168: 1813-1822, 2002. [PubMed: 11823514, related citations] [Full Text]

  23. Yoshimura, A., Gemma, A., Hosoya, Y., Komaki, E., Hosomi, Y., Okano, T., Takenaka, K., Matuda, K., Seike, M., Uematsu, K., Hibino, S., Shibuya, M., Yamada, T., Hirohashi, S., Kudoh, S. Increased expression of the LGALS3 (galectin 3) gene in human non-small-cell lung cancer. Genes Chromosomes Cancer 37: 159-164, 2003. [PubMed: 12696064, related citations] [Full Text]

  24. Zhou, Y., He, C. H., Yang, D. S., Nguyen, T., Cao, Y., Kamle, S., Lee, C., Gochuico, B. R., Gahl, W. A., Shea, B. S., Lee, C. G., Elias, J. A. Galectin-3 interacts with the CHI3L1 axis and contributes to Hermansky-Pudlak syndrome lung disease. J. Immun. 200: 2140-2153, 2018. [PubMed: 29427412, related citations] [Full Text]


Bao Lige - updated : 03/10/2020
Bao Lige - updated : 11/13/2018
Paul J. Converse - updated : 10/17/2011
Patricia A. Hartz - updated : 12/26/2007
Patricia A. Hartz - updated : 11/2/2007
Patricia A. Hartz - updated : 10/18/2007
Patricia A. Hartz - updated : 6/2/2006
Marla J. F. O'Neill - updated : 2/21/2005
Ada Hamosh - updated : 2/2/2005
Marla J. F. O'Neill - updated : 9/1/2004
John A. Phillips, III - updated : 9/2/2003
Victor A. McKusick - updated : 8/7/2003
John A. Phillips, III - updated : 4/8/2003
Patricia A. Hartz - updated : 12/17/2002
Paul J. Converse - updated : 3/25/2002
Paul J. Converse - updated : 9/22/2000
Victor A. McKusick - updated : 6/8/1999
Victor A. McKusick - updated : 9/16/1997
Creation Date:
Victor A. McKusick : 10/16/1990
mgross : 03/10/2020
carol : 11/14/2018
mgross : 11/13/2018
carol : 08/18/2016
carol : 07/13/2016
mgross : 11/3/2011
terry : 10/17/2011
wwang : 12/26/2007
mgross : 11/7/2007
terry : 11/2/2007
mgross : 10/23/2007
mgross : 10/23/2007
terry : 10/18/2007
mgross : 6/8/2006
terry : 6/2/2006
terry : 3/16/2005
terry : 2/21/2005
carol : 2/18/2005
terry : 2/2/2005
carol : 10/27/2004
carol : 9/2/2004
terry : 9/1/2004
alopez : 9/2/2003
tkritzer : 8/12/2003
terry : 8/7/2003
cwells : 5/1/2003
terry : 4/8/2003
mgross : 1/3/2003
terry : 12/17/2002
mgross : 3/26/2002
terry : 3/25/2002
mgross : 9/22/2000
jlewis : 6/18/1999
jlewis : 6/17/1999
terry : 6/8/1999
dkim : 7/21/1998
dholmes : 4/14/1998
jenny : 9/19/1997
terry : 9/16/1997
mark : 8/19/1997
mark : 5/21/1996
mark : 6/16/1995
supermim : 3/16/1992
carol : 10/16/1990

* 153619

LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 3; LGALS3


Alternative titles; symbols

MACROPHAGE GALACTOSE-SPECIFIC LECTIN; MAC2
GALACTOSIDE-BINDING PROTEIN; GALBP
GALECTIN 3; GAL3


Other entities represented in this entry:

GALECTIN 3 INTERNAL GENE, INCLUDED; GALIG, INCLUDED

HGNC Approved Gene Symbol: LGALS3

Cytogenetic location: 14q22.3   Genomic coordinates (GRCh38) : 14:55,129,252-55,145,430 (from NCBI)


TEXT

Cloning and Expression

The murine Mac2 protein is a galactose- and IgE-binding lectin secreted by inflammatory macrophages. Cherayil et al. (1990) cloned and characterized a cDNA representing the human homolog. The amino acid sequence derived therefrom indicated that the protein is evolutionarily highly conserved, especially in the C-terminal lectin domain. Human MAC2 synthesized in vitro is recognized by a monoclonal antibody to mouse Mac2 and behaves like a galactose-specific lectin in its binding to the desialylated glycoprotein asialofetuin. It also binds to purified laminin (see 150320), indicating a potential role in macrophage extracellular matrix interactions. MAC2 is also known as galectin-3 (LGALS3), as mentioned in Madsen et al. (1995).

From a human fibrosarcoma cDNA library, Raz et al. (1991) cloned a galactoside-binding protein with a molecular weight of 31,000. The deduced 242-amino acid protein has the characteristics of a carbohydrate-binding protein. The deduced amino acid sequence contains 95 residues at the N terminus that are homologous to the predicted amino acid sequence of the second exon of the oncogene LMYC (164850).

Huflejt et al. (1997) found that LGALS3 and LGALS4 (602518) have very different cellular localizations in human colon adenocarcinoma T84 cells, suggesting that these LGALSs have different targeting mechanisms, ligands, and functions. In confluent T84 cells, LGALS3 is concentrated mainly at the apical membrane in large granular inclusions. In subconfluent T84 cells, it is distributed along most of the cell periphery and is concentrated in the posterior part of lamellipodia.

By RT-PCR of a human osteosarcoma cell line, Raimond et al. (1995) identified galectin-3 transcripts initiated from the promoter upstream of exon 1 and from the internal promoter within intron 2. Using RT-PCR and EST database analysis, Guittaut et al. (2001) obtained transcripts originating from the internal promoter in intron 2 of LGALS3 from several cDNA libraries. They concluded that these transcripts arise from a gene embedded within LGALS3 that they called 'galectin-3 internal gene,' or GALIG. The GALIG transcripts contain 2 overlapping ORFs, ORF1 and ORF2, that initiate in exon 3 of LGALS3 and are out-of-frame relative to the LGALS3 coding sequence. RT-PCR detected variable and tissue-specific expression of LGALS3 and GALIG transcripts. GALIG transcripts showed highest expression in peripheral blood leukocytes, but overall they were much less abundant than LGALS3 transcripts. In transfected osteosarcoma cells, fluorescence-tagged ORF1 localized to cytosol and nucleus, and fluorescence-tagged ORF2 localized to mitochondria.


Gene Function

Galectin-3 is expressed in various tissues and organs, but is significantly absent in normal hepatocytes. However, evaluation of patient liver biopsies for galectin-3 expression revealed that hepatocellular carcinoma (HCC) frequently expressed significant levels of this lectin; 76% were immunohistochemically positive. Further investigations showed that galectin-3 expression in HCC is independent of whether the patient had prior hepatitis B virus infection (Hsu et al., 1999). Hsu et al. (1999) suggested that deregulated expression of galectin-3 can result in tumor transformation and invasiveness, or confer propensity for tumor cell survival.

Using reporter gene assays, Raimond et al. (1995) showed that p53 (TP53; 191170) downregulated expression of the GALIG promoter when cotransfected into a human osteosarcoma cell line.

In the thyroid, expression of galectin-3 protein had been described in differentiated follicular cancer, suggesting that the immunohistochemical study of galectin-3 may be a potential marker of malignancy in thyroid neoplasms. Martins et al. (2002) analyzed galectin-3 protein and mRNA expression in thyroid tissues from 87 patients with histomorphologic diagnosis of multinodular goiter (MNG), follicular adenoma, follicular carcinoma, papillary carcinoma, and 5 normal tissues. Galectin-3 mRNA expression was detected by RT-PCR. Their results showed that the majority of carcinomas expressed galectin-3 protein (follicular, 90%; papillary, 100%). However, in contrast to the previously published data, benign lesions also expressed galectin-3 (adenoma, 45%; MNG, 17%). The authors showed by RT-PCR that thyroid tissues with diagnosis of adenoma and MNG expressed galectin-3 mRNA. Although the galectin-3 immunostaining demonstrated a sensitivity of 93.8% in the identification of cancer, the accuracy in the distinction between benign and malignant tissues was 77.0%. This accuracy was even lower (68.6%) when galectin-3 expression in follicular adenoma was compared with follicular carcinoma.

Using micro-Boyden chamber analysis, Sano et al. (2000) determined that LGALS3 has chemoattractant activity not for eosinophils, like LGALS9 (601879), but for monocytes and mature macrophages. At high concentrations LGALS3 activity is chemotactic, i.e., cells migrate towards the attractant, whereas at low concentrations it is chemokinetic, i.e., it enhances movement of cells in all directions. Sano et al. (2000) found that the chemoattractant activity is inhibited by lactose, indicating that the C-terminal lectin domain of LGALS3 is required. A C-terminal domain fragment was unable to mediate chemoattraction, suggesting that the N-terminal domain is also necessary for activity. Both migration and increased intracellular calcium concentration were pertussis toxin sensitive and therefore probably mediated by a G protein-coupled receptor. The authors determined that LGALS3 does not, however, use the chemokine receptors CCR1 (601159), CCR2 (601267), CCR5 (601373), and CXCR4 (162643).

Yoshimura et al. (2003) found increased expression of the LGALS3 gene in human nonsmall cell lung cancer, and suggested that it may play a role in the process of metastasis in this malignancy but not in small cell lung cancer. They considered that LGALS3 may be a phenotypic marker that excludes small cell lung cancer and a novel target molecule in therapy of nonsmall cell lung cancer.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (HRAS, 190020; NRAS, 164790; KRAS, 190070) mutations and PAX8 (167415)-PPARG (601487) rearrangements using molecular methods and for galectin-3 and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.

Ohshima et al. (2003) found that galectin-3 mRNA and protein are expressed throughout synovial tissue in rheumatoid arthritis (RA; 180300) and that both galectin-3 and its binding protein are found at sites of joint destruction. In addition, levels of galectin-3 in serum and synovial fluid as well as levels of its binding protein in synovial fluid were significantly elevated in RA compared to osteoarthritis and healthy controls (p less than 0.001). Serum galectin-3 levels correlated significantly with C-reactive protein levels (p less than 0.001), and levels of its binding protein correlated with levels of cartilage oligomeric matrix protein in both serum and synovial fluid (p less than 0.001 and 0.005, respectively). In vitro, RA synovial fibroblasts showed an increased release of galectin-3 into culture medium but decreased secretion of its binding protein. Ohshima et al. (2003) concluded that galectin-3 and its binding protein are not only involved in inflammation but also contribute to the activation of synovial fibroblasts, and thus represent markers of disease activity in rheumatoid arthritis.

Partridge et al. (2004) reported that expression of Mgat5 (601774) sensitized mouse cells to multiple cytokines. Gal3 crosslinked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor-beta receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5 expression in mammary carcinoma was rate limiting for cytokine signaling and consequently for epithelial-mesenchymal transition, cell motility, and tumor metastasis. Mgat5 also promoted cytokine-mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Partridge et al. (2004) concluded that conditional regulation of N-glycan processing drives synchronous modification of cytokine receptors, which balances their surface retention against loss through endocytosis.

Henderson et al. (2006) found that galectin-3 was upregulated in established human fibrotic liver disease. In experimental hepatic fibrosis in rats, galectin-3 upregulation was associated with induction and resolution of fibrosis. Disruption of the galectin-3 gene blocked myofibroblast activation and procollagen I expression in vitro and in vivo and attenuated liver fibrosis. Exogenous recombinant galectin-3 reversed this abnormality. Following liver injury and inflammation, hepatic fibrosis was reduced in galectin-3-null mice compared with wildtype mice. Tgf-beta (190180) failed to activate galectin-3-null mouse hepatic stellate cells, indicating that galectin-3 is required for Tgf-beta-mediated myofibroblast activation and matrix production.

Both MUC1 (158340) and galectin-3 are widely expressed in human carcinomas. Ramasamy et al. (2007) showed that, following glycosylation on asn36, the MUC1 C-terminal subunit (MUC1C) induced galectin-3 expression by suppressing expression of miRNA322 (MIRN322; 300682), a microRNA that destabilizes galectin-3 transcripts. In turn, galectin-3 bound MUC1C at the glycosylated asn36 site and formed a bridge between MUC1 and epidermal growth factor receptor (EGFR; 131550), integrating MUC1 with EGF (131530) signaling.

Mazurek et al. (2007) stated that GAL3 may exert anti- or pro- apoptotic activity depending on the cell type and the nature of the stimulus. They showed that introduction of phosphorylated GAL3 into a GAL3-null human breast cancer cell line promoted apoptotic cell death through TRAIL (TNFSF10; 603598), a member of the tumor necrosis factor family that transmits death signals through death domain-containing receptors. Downstream, TRAIL sensitivity depended upon induction of PTEN (601728) expression, resulting in inactivation of the PI3K (see PIK3CA; 171834)/AKT (AKT1; 164730) survival pathway.

Chen et al. (2009) reported that Cd4 (186940)-positive T cells from mice lacking Gal3 secreted more Ifng (147570) and Il4 (147780) than wildtype cells after engagement of the T-cell receptor (TCR). In activated mouse and human T cells, GAL3 was recruited to the cytoplasmic side of the immunologic synapse, primarily in the peripheral supramolecular activation cluster (SMAC). Wildtype mouse T cells formed central SMAC less effectively and adhered to antigen-presenting cells less firmly than Gal3 -/- cells, suggesting that GAL3 is involved in stabilizing the immunologic synapse. Yeast 2-hybrid analysis of a human T-cell cDNA library, followed by coimmunoprecipitation and immunofluorescence analyses, identified ALIX (PDCD6IP; 608074) as a GAL3 binding partner and showed that ALIX translocated to the immunologic synapse in activated T cells. Chen et al. (2009) concluded that GAL3 is an inhibitory regulator of T-cell activation and that it functions intracellularly by promoting TCR downregulation, possibly through modulation of ALIX function at the immunologic synapse.

Using real-time quantitative PCR, Mammen et al. (2017) found significantly increased Gal3, Il17 (see 603149), and Tgf-beta-1 gene expression in lung tissue of ovalbumin (OVA)-sensitized Timp1 (305370)-knockout mice, a model of allergic asthma, compared with sham-treated wildtype mice. ELISA revealed significantly increased Gal3 protein levels in serum of OVA-sensitized wildtype and Timp1-knockout mice compared with sham-treated wildtype and Timp1-knockout mice, but the increase was higher in the Timp1-knockout mice. Real-time quantitative PCR and Western blot analyses demonstrated increased Gal3 gene and protein expression in lung tissue of OVA-sensitized wildtype and Timp1-knockout mice compared with sham-treated wildtype and Timp1-knockout mice. Knockdown of GAL3 expression in A549 human lung epithelial cells suggested that GAL3 plays a pivotal role in the balance between a proinflammatory response and a protective antiinflammatory response by modulating IL17 levels.

Zhou et al. (2018) found that expression and accumulation of Gal3 increased in lungs during bleomycin-induced fibroproliferative repair in Hps1 (203300)-deficient 'pale ear' mice, a model of Hermansky-Pudlak syndrome-1 (HPS1; 203300), compared with wildtype mice. Fibroblasts and macrophages from pale ear mice expressed and contained more Gal3 than wildtype cells and had a Gal3 trafficking defect that augmented intracellular accumulation of Gal3 and decreased secretion of Gal3 into extracellular space. In contrast, lung epithelial cells did not show induction or production of Gal3 in wildtype or pale ear mice. Comparison of the bleomycin-induced epithelial injury (apoptosis) and fibroproliferative repair (collagen accumulation) responses showed that intracellular Gal3 drove fibroproliferative repair by inhibiting fibroblast apoptosis, increasing fibroblast proliferation and differentiation. Extracellular Gal3, on the other hand, was a potent stimulator of lung epithelial apoptosis and did not produce effects like those of intracellular Gal3. Intracellular Gal3 did not regulate macrophage apoptosis but increased M2-like macrophage differentiation in pale ear mice. Further analysis showed that Gal3 inhibited the antiapoptotic effects of Chi3l1 (601525) to activate antiapoptotic signaling pathways and played a critical role in Chi3l1-induced Wnt (see 606359)/beta-catenin (CTNNB1; 116806) signaling in lung macrophages. Coimmunoprecipitation analysis demonstrated that Gal3 physically interacted with Chi3l1 and its receptor components, thereby abrogating Chi3l1-induced antiapoptotic signaling, augmenting Wnt/beta-catenin signaling, and contributing to development of epithelial cell death and tissue fibrosis in lungs of Hps1-deficient mice.

Using mice and mouse and human cells, Chen et al. (2019) showed that secretion of galectin-3, including serum galectin-3, relied on activation of the NLRP3 (606416) inflammasome. The exosome pathway did not mediate NLRP3 inflammasome-driven galectin-3 secretion. Instead, gasdermin D (GSDMD; 617042) perforated the plasma membrane to allow nonexosomal release of galectin-3. Knockout analysis in mice demonstrated that galectin-3 was an Nlrp3 inflammasome effector that desensitized insulin signaling. Nlrp3 inflammasome-mediated galectin-3 secretion exacerbated insulin resistance in mice.


Gene Structure

Guittaut et al. (2001) reported that the LGALS3 gene contains 6 exons. It has a proximal promoter upstream of exon 1 and a conserved internal promoter within the 5-prime region of intron 2.


Mapping

Raz et al. (1991) mapped the gene encoding galactoside-binding protein, symbolized GALBP by them, to 1p13 by in situ hybridization. Conflicting mapping results were obtained by Raimond et al. (1997), who mapped the LGALS3 gene to 14q21-q22 by fluorescence in situ hybridization and confirmed the location by isotopic hybridization with a tritium-labeled probe. No secondary peak of hybridization was observed by either method on the short arm of chromosome 1 where the gene had been tentatively assigned by Raz et al. (1991). Presumably, the chromosome 14 location is the true one.


Animal Model

Neutrophil extravasation is mediated by ITGB2 (600065) and selectins (e.g., SELE; 131210). Using an in vivo streptococcal pneumonia mouse model, Sato et al. (2002) showed by Western blot analysis an accumulation of galectin-3 in the bronchoalveolar lavage fluid that correlated with the kinetics of neutrophil emigration to alveoli during S. pneumoniae, but not E. coli, infection. Immunohistochemical analysis demonstrated galectin-3 expression on endothelial and epithelial cell layers and interstitial spaces in lung tissue. Functional analysis indicated that galectin-3 promoted neutrophil adhesion to endothelial cells and that this resulted from direct crosslinking of neutrophils and was dependent on galectin-3 oligomerization. Sato et al. (2002) suggested that galectin-3 plays a role in ITGB2-independent neutrophil extravasation during alveolar infection with S. pneumoniae.

Using models of corneal wound healing, Cao et al. (2002) found that reepithelialization of wounds was significantly slower in Gal3-null mice compared with wildtype mice, and the difference was not due to a reduced epithelial cell proliferation rate. Gene expression analysis using cDNA microarrays revealed that healing corneas of Gal3-null mice had reduced levels of Gal7 (600615). Exogenous application of Gal7, but not Gal3, accelerated reepithelialization of wounds in Gal3-null mice. Both Gal3 and Gal7 accelerated corneal wound healing in wildtype mice. Cao et al. (2002) concluded that both GAL3 and GAL7 play a role in reepithelialization of corneal wounds.

Sano et al. (2003) demonstrated reduced phagocytosis of IgG-opsonized erythrocytes and apoptotic thymocytes in Gal3 -/- macrophages compared to wildtype. Gal3-null mice showed attenuated phagocytic clearance of apoptotic thymocytes by peritoneal macrophages and reduced IgG-mediated phagocytosis of erythrocytes by Kupffer cells in a mouse model of autoimmune hemolytic anemia. Extracellular Gal3 did not contribute to phagocytosis. Sano et al. (2003) concluded that GAL3 may play an important role in both innate and adaptive immunity by contributing to phagocytic clearance of microorganisms and apoptotic cells.


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Contributors:
Bao Lige - updated : 03/10/2020
Bao Lige - updated : 11/13/2018
Paul J. Converse - updated : 10/17/2011
Patricia A. Hartz - updated : 12/26/2007
Patricia A. Hartz - updated : 11/2/2007
Patricia A. Hartz - updated : 10/18/2007
Patricia A. Hartz - updated : 6/2/2006
Marla J. F. O'Neill - updated : 2/21/2005
Ada Hamosh - updated : 2/2/2005
Marla J. F. O'Neill - updated : 9/1/2004
John A. Phillips, III - updated : 9/2/2003
Victor A. McKusick - updated : 8/7/2003
John A. Phillips, III - updated : 4/8/2003
Patricia A. Hartz - updated : 12/17/2002
Paul J. Converse - updated : 3/25/2002
Paul J. Converse - updated : 9/22/2000
Victor A. McKusick - updated : 6/8/1999
Victor A. McKusick - updated : 9/16/1997

Creation Date:
Victor A. McKusick : 10/16/1990

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