Biology:Galectin-3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 (Gal-3) is also a member of the beta-galactoside-binding protein family that plays an important role in cell-cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, apoptosis.

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]

Galectin-3 associates with the primary cilium and modulates renal cyst growth in congenital polycystic kidney disease.[13]

The functional roles of galectins in cellular response to membrane damage are rapidly expanding.[14][15][16] It has recently shown that Galectin-3 recruits ESCRTs to damaged lysosomes so that lysosomes can be repaired.[15]

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.[17][18][19] Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 and GR-MD-02 have the potential to treat fibrosis.[19]

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.[20][21] 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.[22]

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.[23] 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.[24]

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.[25]

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.[25]

The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated.[26] Of note, galectin-3 has been suggested to play important roles in cancer metastasis.[27]

Clinical applications

Cardiovascular risk indicator

Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by BG Medicine and marketed by Abbott, helping to determine which patients are most at risk for the disease. This test is also offered on the VIDAS platform marketed by bioMérieux.[28] 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.[29]

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.[30] 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 pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development.[30]

Drug development

Galecto Biotech in Sweden is focused on developing drugs targeting galectin-3 to treat fibrosis, specifically idiopathic pulmonary fibrosis.[31] Galectin Therapeutics in the United States is also targeting galectins for clinical applications. Preclinical studies demonstrate that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis.[32] Galectin Therapeutics galectin-3 inhibitor GR-MD-02 (belapectin) is currently in human clinical trials for nonalcoholic steatohepatitis (NASH) and for increasing the effectiveness and reducing side effects of cancer immunotherapy.[33][34][35]

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.[36] One approach to cancers with high galectin-3 expression is to inhibit galectin-3 to enhance treatment response.[37]

Interactions

LGALS3 has been shown to interact with LGALS3BP.[38][39][40]

In melanocytic cells LGALS3 gene expression may be regulated by MITF.[41]

References

  1. ↑ "Molecular cloning and chromosomal mapping of a human galactoside-binding protein". Cancer Research 51 (8): 2173–8. April 1991. PMID 2009535. 
  2. ↑ "Galectins. Structure and function of a large family of animal lectins". The Journal of Biological Chemistry 269 (33): 20807–10. August 1994. doi:10.1016/S0021-9258(17)31891-4. PMID 8063692. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Galectin-3: an open-ended story". Biochimica et Biophysica Acta (BBA) - General Subjects 1760 (4): 616–35. April 2006. doi:10.1016/j.bbagen.2005.12.020. PMID 16478649. 
  4. ↑ 4.0 4.1 "Entrez Gene: LGALS3 lectin, galactoside-binding, soluble, 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3958. 
  5. ↑ 5.0 5.1 "Intracellular functions of galectins". Biochimica et Biophysica Acta (BBA) - General Subjects 1572 (2–3): 263–73. September 2002. doi:10.1016/S0304-4165(02)00313-6. PMID 12223274. 
  6. ↑ 6.0 6.1 "Galectinomics: finding themes in complexity". Biochimica et Biophysica Acta (BBA) - General Subjects 1572 (2–3): 209–31. September 2002. doi:10.1016/S0304-4165(02)00310-0. PMID 12223271. 
  7. ↑ 7.0 7.1 "The regulation of inflammation by galectin-3". Immunological Reviews 230 (1): 160–71. July 2009. doi:10.1111/j.1600-065X.2009.00794.x. PMID 19594635. .
  8. ↑ "Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21-22". Mammalian Genome 8 (9): 706–7. September 1997. doi:10.1007/s003359900548. PMID 9271684. 
  9. ↑ 9.0 9.1 9.2 "Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction". Circulation 110 (19): 3121–8. November 2004. doi:10.1161/01.CIR.0000147181.65298.4D. PMID 15520318. 
  10. ↑ "Galectin-3 mediates post-ischemic tissue remodeling". Brain Research 1288: 116–24. September 2009. doi:10.1016/j.brainres.2009.06.073. PMID 19573520. 
  11. ↑ "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. Heart and Circulatory Physiology 296 (2): H404-12. February 2009. doi:10.1152/ajpheart.00747.2008. PMID 19098114. 
  12. ↑ "The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients". Clinica Chimica Acta; International Journal of Clinical Chemistry 409 (1–2): 96–9. November 2009. doi:10.1016/j.cca.2009.09.001. PMID 19747906. 
  13. ↑ "Galectin-3 associates with the primary cilium and modulates cyst growth in congenital polycystic kidney disease". The American Journal of Pathology 169 (6): 1925–38. December 2006. doi:10.2353/ajpath.2006.060245. PMID 17148658. 
  14. ↑ "Galectins Control mTOR in Response to Endomembrane Damage". Molecular Cell 70 (1): 120–135.e8. April 2018. doi:10.1016/j.molcel.2018.03.009. PMID 29625033. 
  15. ↑ 15.0 15.1 "Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal". Developmental Cell 52 (1): 69–87.e8. January 2020. doi:10.1016/j.devcel.2019.10.025. PMID 31813797. 
  16. ↑ "AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System". Molecular Cell 77 (5): 951–969.e9. January 2020. doi:10.1016/j.molcel.2019.12.028. PMID 31995728. 
  17. ↑ "Galectin-3 regulates myofibroblast activation and hepatic fibrosis". Proceedings of the National Academy of Sciences of the United States of America 103 (13): 5060–5. March 2006. doi:10.1073/pnas.0511167103. PMID 16549783. Bibcode: 2006PNAS..103.5060H. 
  18. ↑ "Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis". The American Journal of Pathology 172 (2): 288–98. February 2008. doi:10.2353/ajpath.2008.070726. PMID 18202187. 
  19. ↑ 19.0 19.1 "Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3". American Journal of Respiratory and Critical Care Medicine 185 (5): 537–46. March 2012. doi:10.1164/rccm.201106-0965OC. PMID 22095546. 
  20. ↑ "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. September 2006. doi:10.1016/j.jacc.2006.03.061. PMID 16979009. 
  21. ↑ "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. May 2010. doi:10.1007/s00392-010-0125-y. PMID 20130888. 
  22. ↑ "Galectin-3: a novel mediator of heart failure development and progression". European Journal of Heart Failure 11 (9): 811–7. September 2009. doi:10.1093/eurjhf/hfp097. PMID 19648160. 
  23. ↑ "Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)". European Heart Journal 33 (18): 2290–6. September 2012. doi:10.1093/eurheartj/ehs077. PMID 22513778. 
  24. ↑ "Galectin-3 and left ventricular reverse remodelling after surgical mitral valve repair". European Journal of Heart Failure 15 (9): 1011–8. September 2013. doi:10.1093/eurjhf/hft056. PMID 23576289. 
  25. ↑ 25.0 25.1 "Galectin-3--a jack-of-all-trades in cancer". Cancer Letters 313 (2): 123–8. December 2011. doi:10.1016/j.canlet.2011.09.003. PMID 21974805. 
  26. ↑ "Galectins as modulators of tumour progression". Nature Reviews. Cancer 5 (1): 29–41. January 2005. doi:10.1038/nrc1527. PMID 15630413. 
  27. ↑ "A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis". Nature Communications 3 (3): 1122. 2012. doi:10.1038/ncomms2128. PMID 23047680. Bibcode: 2012NatCo...3.1122R. 
  28. ↑ Ross, D. "Abbott's Galectin-3 Test Provides Doctors in Europe with New Tool for Assessing the Prognosis of Chronic Heart Failure Patient". http://www.abbott.com/press-release/abbotts-galectin3-test-provides-doctors-in-europe-with-new-tool-for-assessing-the-prognosis-of-chr.htm. 
  29. ↑ Brechka, Nicole (2009). Putting the Squeeze on Cancer. http://www.betternutrition.com/citrus-pectin-cancer-fighter/columns/favoritethings/1086. Retrieved 28 November 2013. 
  30. ↑ 30.0 30.1 "Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis". Circulation: Heart Failure 6 (1): 107–17. January 2013. doi:10.1161/circheartfailure.112.971168. PMID 23230309. 
  31. ↑ "Galecto Biotech". Nature Biotechnology 31 (6): 481. June 2013. doi:10.1038/nbt0613-481. PMID 23752421. 
  32. ↑ "Galectin Therapeutics' Preclinical Data Published in PLOS ONE Show Its Galectin Inhibitors Reverse Cirrhosis and Significantly Reduce Fibrosis and Portal Hypertension". Globe Newswire. http://phx.corporate-ir.net/phoenix.zhtml?c=135403&p=irol-newsArticle&ID=1863329&highlight=. 
  33. ↑ "Therapeutic Landscape for NAFLD in 2020". Gastroenterology 158 (7): 1984–1998.e3. May 2020. doi:10.1053/j.gastro.2020.01.051. PMID 32061596. 
  34. ↑ "Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review". Journal of the American College of Cardiology 75 (21): 2726–2737. June 2020. doi:10.1016/j.jacc.2020.03.067. PMID 32466889. 
  35. ↑ "Galectins in prostate and bladder cancer: tumorigenic roles and clinical opportunities". Nature Reviews. Urology 16 (7): 433–445. July 2019. doi:10.1038/s41585-019-0183-5. PMID 31015643. 
  36. ↑ "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): e26150. 19 October 2011. doi:10.1371/journal.pone.0026150. PMID 22039439. PMC 3198435. Bibcode: 2011PLoSO...626150I. http://pubmed.cn/22039439. 
  37. ↑ "Immunhistochemical [sic] expression of galectin-3 in cancer: a review of the literature". Turk Patoloji Dergisi. 1 28 (1): 1–10. March 2011. doi:10.5146/tjpath.2012.01090. PMID 22207425. 
  38. ↑ "Mac-2-binding glycoproteins. Putative ligands for a cytosolic beta-galactoside lectin". The Journal of Biological Chemistry 266 (28): 18731–6. October 1991. doi:10.1016/S0021-9258(18)55124-3. PMID 1917996. 
  39. ↑ "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. July 1993. doi:10.1016/S0021-9258(19)85233-X. PMID 8390986. 
  40. ↑ "Glycoprotein 90K/MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation". International Journal of Cancer 91 (2): 167–72. January 2001. doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1022>3.3.co;2-q. PMID 11146440. 
  41. ↑ "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–76. December 2008. 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.



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