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Galectins

BioFiles 2007, 2.1, 21.

Galectins are a family of animal carbohydrate binding proteins; the name is from their description as β-galactoside-specific lectins. They have been strongly implicated in inflammation and cancer and may be useful as targets for the development of new antiinflammatory and anticancer therapies.

Galectins occur at high concentration in a limited range of cell types, different for each galectin. Galectins bind to sugar molecules on the surface of cells. All galectins bind lactose and other β-galactosides, but they differ in their affinity for more complex saccharides.1 The galectins are defined by their structural similarities in their carbohydrate recognition domains (CRD) and by their affinity for β-galactosides; fourteen human members have been reported so far.2The galectins have been classified into three classes, prototype, chimera, and tandem-repeat galectins. The prototype galectins (-1, -2, -5, -7, -10, -11, -13, -14) all contain one CRD and are either monomers or noncovalent homodimers. The only chimera galectin currently identified (galectin-3) contains one CRD connected to a non-lectin domain. The tandem-repeat galectins (-4, -6, -8, -9, -12) consist of two CRDs joined by a linker peptide.

Extracellular galectins crosslink cell-surface and extracellular glycoproteins and may thereby modulate cell adhesion and induce intracellular signals. Galectins may also bind intracellular noncarbohydrate ligands and have intracellular regulatory roles in processes such as RNA splicing, apoptosis, and, suggested most recently, the cell cycle.1

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Galectin-1

Galectin-1 has been implicated in metastasis and aggregation of cancer cells based on its association with the glycoprotein 90K.4,5 It has been shown to induce apoptosis of activated T-cells,6 T-leukemia cell lines,7 breast,8 colon,9 and prostate10cancer cells. Other activities of galectin-1 include cell differentiation and inhibition of CD45 protein phosphatase activity. Galectin-1 binds CD45, CD3, and CD4 in addition to b-galactoside. Galectin-1 bound in the extracellular matrix can induce cell death of adherent T cells at a ten-fold lower concentration than soluble galectin-1.11 Galectin-1 may play a significant role in cancer through apoptosis, cell adhesion and migration, regulation of the cell cycle, and tumor evasion of immune responses.12,13

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Galectin-3

Galectin-3, also called Mac-2, L29, CBP35 and εBP, is a chimera galectin that is expressed in tumor cells, macrophages, activated T cells, epithelial cells, and fibroblasts. It binds a variety of matrix glycoproteins including laminin and fibronectin. Intracellularly, galectin-3 acts to prevent apoptosis. Depending on the cell type, galectin-3 can be localized in the extracellular matrix, the cell surface, in the cytoplasm, or in the nucleus. Galectin-3 has been shown to exhibit proinflammatory activities in vitro and in vivo; it induces pro-inflammatory and inhibits Th2 type cytokine production.3 High levels of circulating galectin-3 have been shown to correlate with the malignancy potential of several types of cancer. Galectin-3 is known to play a role in tumor growth, metastasis, and cell-to-cell adhesion. It also serves as a preferred substrate for matrix metalloproteinase-9 (MMP-9).14 Human and mouse Galectin-3 share approximately 80% homology in their amino acid sequence.15

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Galectin-3C

Galectin-3C is a truncated form of galectin-3 that contains the carboxy-terminus carbohydrate-binding domain. Recombinant galectin-3C competes with endogenous galactin-3 for carbohydrate binding sites and acts as a negative inhibitor of galectin-316 in promoting cell adhesion17 and cell signaling. Galectin-3C has been found to be effective in reducing metastases and tumor volumes and weights in primary tumors in an orthotropic nude mouse model of human breast cancer.18

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Galectin-8

Galectin-8, also known as prostate carcinoma tumor antigen 1 (PCTA1) in human, is a tandem repeat-type galectin. High levels of circulating galectin-8 have been shown to correlate with lung carcinomas, certain forms of prostate carcinomas, as well as other tumor cells.19 It binds to a subset of cell surface integrins to modulate ECM-integrin interactions. It acts as a physiological modulator of cell adhesion and cellular growth, and may be involved in neoplastic transformation.20-22 Human and mouse galectin-8 share approximately 80% homology in their amino acid sequence.15

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Materials

 

     

References

  1. Leffler, H., Results Probl. Cell Differ. 33:57-83 (2001).
  2. Cooper, D.N., Biochim. Biophys. Acta, 1572, 209-231 (2002).
  3. Rabinovich, G.A., et al., Trends Immunol., 23, 313-320 (2002).
  4. Grassadonia, A., et al., Glycoconj. J., 19, 551-6 (2004).
  5. Tinari, N., et al., Int. J. Cancer, 91, 167-72 (2001).
  6. Pace, K.E., et al., Methods Enzymol., 363, 499-518 (2003).
  7. Couraud, P.O., et al., J. Biol. Chem., 64, 1310-6 (1989).
  8. Wiest, I., et al., Anticancer Res., 25, 1575-80 (2005).
  9. Horiguchi, N., et al., J. Biochem. (Tokyo), 134, 869-74 (2003).
  10. Ellerhorst, J., et al., Int. J. Oncol., 14, 225-32 (1999).
  11. He, J., and Baum, L.G., J. Biol. Chem., 279, 4705-12 (2004).
  12. Rabinovich, G.A., Br. J. Cancer, 92, 1188-92 (2005).
  13. Camby, I., et al., Glycobiology, 16, 137R-157R (2006).
  14. Ortega N., et al., Mol Biol Cell, 16, 3028-3039 (2005).
  15. Bidon N., et al., Gene, 274, 253-262 (2001).
  16. Liu, F.T., et al., Biochemistry, 35, 6073-9 (1996).
  17. Ochieng, J., et al., Biochim. Biophys. Acta, 1379, 97-106 (1998).
  18. John, C.M., et al., Clin. Cancer Research, 9, 2374-2383 (2003).
  19. Rabinovich, A. et al., J. Leukocyte Biology 71, 741 (2002).
  20. Levy, Y., et al., J. Biol. Chem., 17, 31285-31295 (2001).
  21. Hadari, Y.R., et al., J. Cell Sci., 113, 2385-2397 (2000).
  22. Camby, I., et al., Brain Pathol., 11, 12-26 (2001).

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