Galectin-3

Lectin, galactoside-binding, soluble, 3

PDB rendering based on 1a3k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsLGALS3 ; CBP35; GAL3; GALBP; GALIG; L31; LGALS2; MAC2
External IDsOMIM: 153619 MGI: 96778 HomoloGene: 37608 ChEMBL: 4531 GeneCards: LGALS3 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez395816854
EnsemblENSG00000131981ENSMUSG00000050335
UniProtP17931D3YVT4
RefSeq (mRNA)NM_001177388NM_001145953
RefSeq (protein)NP_001170859NP_001139425
Location (UCSC)Chr 14:
55.12 – 55.15 Mb		Chr 14:
47.37 – 47.39 Mb
PubMed search

Galectin-3 is a protein that in humans is encoded by the LGALS3 gene.[1][2] Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified.[3][4]

Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides.[3][5][6][7]

Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22.[3][8] Galectin-3 is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space.[3][5][6]

Function

Galectin-3 has an affinity for beta-galactosides and exhibits antimicrobial activity against bacteria and fungi.[4]

This protein has been shown to be involved in the following biological processes: cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis.[3] Given galectin-3’s broad biological functionality, it has been demonstrated to be involved in cancer, inflammation and fibrosis, heart disease, and stroke.[3][7][9][10] Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and Ventricular remodeling.[9][11][12]

Clinical significance

Fibrosis

A correlation between galectin-3 expression levels and various types of fibrosis has been found. Galectin-3 is upregulated in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In several studies with mice deficient in or lacking galectin-3, conditions that caused control mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely.[13][14][15] Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 has the potential to treat fibrosis.[15]

Cardiovascular disease

Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations.[16][17] In normal human, murine, and rat cells galectin-3 levels are low. However as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium.[18]

Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies. For instance, galectin-3 levels could be used in early detection of failure-prone hearts and lead to intervention strategies including broad spectrum anti-inflammatory agents.[9] One study concluded that individuals with systolic heart failure of ischaemic origin and elevated galectin-3 levels may benefit from statin treatment.[19] Galectin-3 has also been associated as a factor promoting ventricular remodeling following mitral valve repair, and may identify patients requiring additional therapies to obtain beneficial reverse remodeling.[20]

Cancer

The wide variety of effects of galectin-3 on cancerous cells are due to the unique structure and various interaction properties of the molecule. Overexpression and changes in the localization of galectin-3 molecules affects the prognosis of the patient and targeting the actions of galectin-3 poses a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment.

Overexpression and changes in sub- and inter-cellular localization of galectin-3 are commonly seen in cancerous conditions. The many interaction and binding properties of galectin-3 influence various cell activities based on its location. Altered galectin-3 expression can affect cancer cell growth and differentiation, chemoattraction, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis.[21]

Galectin-3 overexpression promotes neoplastic transformation and the maintenance of transformed phenotypes as well as enhances the tumour cell's adhesion to the extracellular matrix and increase metastatic spreading. Galectin-3 can be either an inhibitory or a promoting apoptotic depending on its sub-cellular localization. In immune regulation, galectin-3 can regulate immune cell activities and helps contribute to the tumour cell's evasion of the immune system. Galectin-3 also helps promote angiogenesis.[21]

The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated.[22] Of note, galectin-3 has been suggested to play important roles in cancer metastasis.[23]

Clinical applications

As a drug target to treat fibrosis

Galectin-3 is upregulated in patients with idiopathic pulmonary fibrosis. The cells that receive galectin-3 stimulation (fibroblasts, epithelial cells, and myofibroblasts) upregulated the formation of fibrosis and collagen formation.[24] Fibrosis is necessary in many aspects of intrabody regeneration. The myocardial lining constantly undergoes necessary fibrosis, and the inhibition of galectin-3 interferes with myocardial fibrogenesis. A study concluded that drugs binding to galectin-3 will benefit those who have too much fibrosis on the heart, but it might potentially backfire for those who need heart restructuring.[24]

Galecto Biotech is a research company focused on developing drugs using galectin-3 in treatment for fibrosis, specifically idiopathic pulmonary fibrosis.[25] Galectin Therapeutics in the United States is also using galectins for their research, finding recently that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis in mice.[26] Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by Abbott and BG Medicine, helping to determine which patients are most at risk for the disease.[27] Pecta-Sol C binds to galectin-3 binding sites on the surfaces of cells as a preventative measure created by Isaac Eliaz in conjunction with EcoNugenics.[28]

Biomarkers

Galectin-3 is increasingly being used as a diagnostic marker for different cancers. It can be screened for and used as a prognostic factor to predict the progression of the cancer. Galectin-3 has varying effects in different types of cancer.[29] One approach to cancers with high galectin-3 expression is to use small molecule inhibition of galectin-3 to enhance treatment response.[30]

Interactions

LGALS3 has been shown to interact with LGALS3BP.[31][32][33]

In melanocytic cells LGALS3 gene expression may be regulated by MITF.[34]

References

  1. ↑ Raz A, Carmi P, Raz T, Hogan V, Mohamed A, Wolman SR (Apr 1991). "Molecular cloning and chromosomal mapping of a human galactoside-binding protein". Cancer Research 51 (8): 2173–8. PMID 2009535.
  2. ↑ Barondes SH, Cooper DN, Gitt MA, Leffler H (Aug 1994). "Galectins. Structure and function of a large family of animal lectins". The Journal of Biological Chemistry 269 (33): 20807–10. PMID 8063692.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Dumic J, Dabelic S, Flögel M (Apr 2006). "Galectin-3: an open-ended story". Biochimica et Biophysica Acta 1760 (4): 616–635. doi:10.1016/j.bbagen.2005.12.020. PMID 16478649. Vancouver style error (help)
  4. ↑ 4.0 4.1 "Entrez Gene: LGALS3 lectin, galactoside-binding, soluble, 3".
  5. ↑ 5.0 5.1 Liu FT, Patterson RJ, Wang JL (Sep 2002). "Intracellular functions of galectins". Biochimica Et Biophysica Acta 1572 (2-3): 263–273. doi:10.1016/S0304-4165(02)00313-6. PMID 12223274.
  6. ↑ 6.0 6.1 Cooper DN (Sep 2002). "Galectinomics: finding themes in complexity". Biochimica Et Biophysica Acta 1572 (2-3): 209–231. doi:10.1016/S0304-4165(02)00310-0. PMID 12223271.
  7. ↑ 7.0 7.1 Henderson NC, Sethi T (Jul 2009). "The regulation of inflammation by galectin-3". Immunological Reviews 230 (1): 160–171. doi:10.1111/j.1600-065X.2009.00794.x. PMID 19594635. .
  8. ↑ Raimond J, Zimonjic DB, Mignon C, Mattei M, Popescu NC, Monsigny M et al. (Sep 1997). "Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21-22". Mammalian Genome 8 (9): 706–707. doi:10.1007/s003359900548. PMID 9271684.
  9. ↑ 9.0 9.1 9.2 Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B et al. (Nov 2004). "Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction". Circulation 110 (19): 3121–3128. doi:10.1161/01.CIR.0000147181.65298.4D. PMID 15520318.
  10. ↑ Yan YP, Lang BT, Vemuganti R, Dempsey RJ (Sep 2009). "Galectin-3 mediates post-ischemic tissue remodeling". Brain Research 1288: 116–124. doi:10.1016/j.brainres.2009.06.073. PMID 19573520.
  11. ↑ Liu YH, D'Ambrosio M, Liao TD, Peng H, Rhaleb NE, Sharma U et al. (Feb 2009). "N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin". American Journal of Physiology 296 (2): H404–12. doi:10.1152/ajpheart.00747.2008. PMC 2643891. PMID 19098114.
  12. ↑ Lin YH, Lin LY, Wu YW, Chien KL, Lee CM, Hsu RB et al. (Nov 2009). "The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients". Clinica Chimica Acta 409 (1-2): 96–99. doi:10.1016/j.cca.2009.09.001. PMID 19747906.
  13. ↑ Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP et al. (Mar 2006). "Galectin-3 regulates myofibroblast activation and hepatic fibrosis". Proceedings of the National Academy of Sciences of the United States of America 103 (13): 5060–5065. doi:10.1073/pnas.0511167103. PMC 1458794. PMID 16549783.
  14. ↑ Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP et al. (Feb 2008). "Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis". The American Journal of Pathology 172 (2): 288–298. doi:10.2353/ajpath.2008.070726. PMC 2312353. PMID 18202187.
  15. ↑ 15.0 15.1 Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T et al. (Mar 2012). "Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3". American Journal of Respiratory and Critical Care Medicine 185 (5): 537–546. doi:10.1164/rccm.201106-0965OC. PMC 3410728. PMID 22095546.
  16. ↑ van Kimmenade RR, Januzzi JL, Ellinor PT, Sharma UC, Bakker JA, Low AF et al. (Sep 2006). "Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure". Journal of the American College of Cardiology 48 (6): 1217–24. doi:10.1016/j.jacc.2006.03.061. PMID 16979009.
  17. ↑ Lok DJ, Van Der Meer P, de la Porte PW, Lipsic E, Van Wijngaarden J, Hillege HL et al. (2010). "Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study". Clinical Research in Cardiology 99 (5): 323–8. doi:10.1007/s00392-010-0125-y. PMC 2858799. PMID 20130888.
  18. ↑ de Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhuisen DJ (Sep 2009). "Galectin-3: a novel mediator of heart failure development and progression". European Journal of Heart Failure 11 (9): 811–817. doi:10.1093/eurjhf/hfp097. PMID 19648160.
  19. ↑ Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P et al. (Sep 2012). "Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)". European Heart Journal 33 (18): 2290–2296. doi:10.1093/eurheartj/ehs077. PMID 22513778.
  20. ↑ Kortekaas KA, Hoogslag GE, de Boer RA, Dokter MM, Versteegh MI, Braun J et al. (Sep 2013). "Galectin-3 and left ventricular reverse remodelling after surgical mitral valve repair". European Journal of Heart Failure 15 (9): 1011–1018. doi:10.1093/eurjhf/hft056. PMID 23576289.
  21. ↑ 21.0 21.1 Newlaczyl AU, Yu LG (Dec 2011). "Galectin-3--a jack-of-all-trades in cancer". Cancer Letters 313 (2): 123–128. doi:10.1016/j.canlet.2011.09.003. PMID 21974805.
  22. ↑ Liu FT, Rabinovich GA (Jan 2005). "Galectins as modulators of tumour progression". Nature Reviews. Cancer 5 (1): 29–41. doi:10.1038/nrc1527. PMID 15630413.
  23. ↑ Reticker-Flynn NE, Malta DF, Winslow MM, Lamar JM, Xu MJ, Underhill GH et al. (2012). "A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis". Nature Communications 3 (3): 1122. doi:10.1038/ncomms2128. PMID 23047680.
  24. ↑ 24.0 24.1 Yu L, Ruifrok WP, Meissner M, Bos EM, van Goor H, Sanjabi B et al. (Jan 2013). "Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis". Circulation. Heart Failure 6 (1): 107–117. doi:10.1161/circheartfailure.112.971168. PMID 23230309.
  25. ↑ Garber K (Jun 2013). "Galecto Biotech". Nature Biotechnology 31 (6): 481. doi:10.1038/nbt0613-481. PMID 23752421.
  26. ↑ "Galectin Therapeutics' Preclinical Data Published in PLOS ONE Show Its Galectin Inhibitors Reverse Cirrhosis and Significantly Reduce Fibrosis and Portal Hypertension". Globe Newswire. Retrieved 28 November 2013.
  27. ↑ Ross, D. "Abbott's Galectin-3 Test Provides Doctors in Europe with New Tool for Assessing the Prognosis of Chronic Heart Failure Patient". Retrieved 28 November 2013.
  28. ↑ Brechka, Nicole (2009). "Putting the Squeeze on Cancer". Retrieved 28 November 2013.
  29. ↑ Idikio HA (19 October 2011). "Galectin-3 and Beclin1/Atg6 genes in human cancers: using cDNA tissue panel, qRT-PCR, and logistic regression model to identify cancer cell biomarkers". PloS One 6 (10): 1–8. doi:10.1371/journal.pone.0026150. PMID 22039439.
  30. ↑ Cay T (March 2011). "Immunhistochemical expression of galectin-3 in cancer: a review of the literature". Türk Patoloji Dergisi. 1 28 (1): 1–10. doi:10.5146/tjpath.2012.01090. PMID 22207425.
  31. ↑ Rosenberg I, Cherayil BJ, Isselbacher KJ, Pillai S (Oct 1991). "Mac-2-binding glycoproteins. Putative ligands for a cytosolic beta-galactoside lectin". The Journal of Biological Chemistry 266 (28): 18731–6. PMID 1917996.
  32. ↑ Koths K, Taylor E, Halenbeck R, Casipit C, Wang A (Jul 1993). "Cloning and characterization of a human Mac-2-binding protein, a new member of the superfamily defined by the macrophage scavenger receptor cysteine-rich domain". The Journal of Biological Chemistry 268 (19): 14245–9. PMID 8390986.
  33. ↑ Tinari N, Kuwabara I, Huflejt ME, Shen PF, Iacobelli S, Liu FT (Jan 2001). "Glycoprotein 90K/MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation". International Journal of Cancer. Journal International Du Cancer 91 (2): 167–72. doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1022>3.3.co;2-q. PMID 11146440.
  34. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO et al. (Dec 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.