Galectin-3

Lectin, galactoside-binding, soluble, 3

PDB rendering based on 1a3k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LGALS3 ; CBP35; GAL3; GALBP; GALIG; L31; LGALS2; MAC2
External IDs OMIM: 153619 MGI: 96778 HomoloGene: 37608 ChEMBL: 4531 GeneCards: LGALS3 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 3958 16854
Ensembl ENSG00000131981 ENSMUSG00000050335
UniProt P17931 D3YVT4
RefSeq (mRNA) NM_001177388 NM_001145953
RefSeq (protein) NP_001170859 NP_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 (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]

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.[14][15][16] 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.[16]

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.[17][18] 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.[19]

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.[20] 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.[21]

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.[22]

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.[22]

The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated.[23] Of note, galectin-3 has been suggested to play important roles in cancer metastasis.[24]

Clinical applications

As an indicator of Cardiovascular Risk

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 is the only marketed test presently to automatically process galectin-3 levels.[25] 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.[26]

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.[27] 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.[27]

Galecto Biotech is another research company focused on developing drugs using galectin-3 in treatment for fibrosis, specifically idiopathic pulmonary fibrosis.[28] 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.[29]

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.[30] One approach to cancers with high galectin-3 expression is to use small molecule inhibition of galectin-3 to enhance treatment response.[31]

Interactions

LGALS3 has been shown to interact with LGALS3BP.[32][33][34]

In melanocytic cells LGALS3 gene expression may be regulated by MITF.[35]

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. 1 2 3 4 5 6 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.
  4. 1 2 "Entrez Gene: LGALS3 lectin, galactoside-binding, soluble, 3".
  5. 1 2 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. 1 2 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. 1 2 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, Legrand A (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. 1 2 3 Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, André S, Crijns HJ, Gabius HJ, Maessen J, Pinto YM (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, André S, Gabius HJ, Carretero OA (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, Chao CL, Wang SS, Hsein YC, Liao LC, Ho YL, Chen MF (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. ↑ pmid = 17148658
  14. ↑ Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, Haslett C, Simpson KJ, Sethi T (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.
  15. ↑ Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP, Liu FT, Hughes J, Sethi T (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.
  16. 1 2 Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T (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.
  17. ↑ van Kimmenade RR, Januzzi JL, Ellinor PT, Sharma UC, Bakker JA, Low AF, Martinez A, Crijns HJ, MacRae CA, Menheere PP, Pinto YM (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.
  18. ↑ Lok DJ, Van Der Meer P, de la Porte PW, Lipsic E, Van Wijngaarden J, Hillege HL, van Veldhuisen DJ (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.
  19. ↑ 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.
  20. ↑ Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, Adourian A, Böhm M, van Veldhuisen DJ, Komajda M, Cleland JG, Wikstrand J, McMurray JJ, Aukrust P (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.
  21. ↑ Kortekaas KA, Hoogslag GE, de Boer RA, Dokter MM, Versteegh MI, Braun J, Marsan NA, Verwey HF, Delgado V, Schalij MJ, Klautz RJ (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.
  22. 1 2 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.
  23. ↑ 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.
  24. ↑ Reticker-Flynn NE, Malta DF, Winslow MM, Lamar JM, Xu MJ, Underhill GH, Hynes RO, Jacks TE, Bhatia SN (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.
  25. ↑ 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.
  26. ↑ Brechka, Nicole (2009). "Putting the Squeeze on Cancer". Retrieved 28 November 2013.
  27. 1 2 Yu L, Ruifrok WP, Meissner M, Bos EM, van Goor H, Sanjabi B, van der Harst P, Pitt B, Goldstein IJ, Koerts JA, van Veldhuisen DJ, Bank RA, van Gilst WH, Silljé HH, de Boer RA (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.
  28. ↑ Garber K (Jun 2013). "Galecto Biotech". Nature Biotechnology 31 (6): 481. doi:10.1038/nbt0613-481. PMID 23752421.
  29. ↑ "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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (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.

This article is issued from Wikipedia - version of the Wednesday, March 09, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.