Biology:Lumican

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

Lumican,[1] also known as LUM, is an extracellular matrix protein that, in humans, is encoded by the LUM gene on chromosome 12.[2][3]

Structure

Lumican is a proteoglycan Class II member of the small leucine-rich proteoglycan (SLRP) family that includes decorin, biglycan, fibromodulin, keratocan, epiphycan, and osteoglycin.[4]

Like the other SLRPs, lumican has a molecular weight of about 40 kilodaltons and has four major intramolecular domains:[5]

  1. a signal peptide of 16 amino acid residues;
  2. a negatively-charged N-terminal domain containing sulfated tyrosine and disulfide bond(s);
  3. ten tandem leucine-rich repeats allowing lumican to bind to other extracellular components such as collagen;
  4. a carboxyl terminal domain of 50 amino acid residues containing two conserved cysteines 32 residues apart.

There are four N-linked sites within the leucine-rich repeat domain of the protein core that can be substituted with keratan sulfate. The core protein of lumican (like decorin and fibromodulin) is horseshoe shaped. This enables it bind to collagen molecules within a collagen fibril, thus helping keep adjacent fibrils apart.[6]

Function

Lumican is a major keratan sulfate proteoglycan of the cornea but is ubiquitously distributed in most mesenchymal tissues throughout the body.[7] Lumican is involved in collagen fibril organization and circumferential growth, corneal transparency, and epithelial cell migration and tissue repair.[2] Corneal transparency is possible due to the exact alignment of collagen fibers by lumican (and keratocan) in the intrafibrillar space.

Clinical significance

Mice that have the lumican gene knocked out (Lum-/-) develop opacities of the cornea in both eyes and fragile skin.[8] The lumican (LUM) gene was thought to be a candidate susceptibility gene for high myopia; however, a meta-analysis showed no association between LUM polymorphism and high myopia susceptibility in all genetic models studied.[9]

Lum knockout mice also have abnormal collagen in their heart tissue, with fewer and thicker fibrils.[10] Mice deficient in both lumican and fibromodulin develop severe tendinopathy (tendon pathology), revealing the importance of these SLRPs in the development of correctly sized and aligned collagen fibers in tendon.[11] Along with other extracellular matrix components, lumican expression was increased in equine flexor tendons six weeks after an injury.[12]

Lumican is present in the extracellular matrix of uteral tissues in fertile women.[13] There is an increase of lumican during the proliferative to secretory phase of the endometrium. In menopausal endometrial tissue, the level of lumican expression decreases and is also low in pathological compared to normal endometrium.

Lumican is highly expressed in pleural effusions (lung fluid) of patients with adenocarcinoma.[14] Its expression was low in cancer cells but high in the extracellular matrix surrounding the tumor. Lumican expression was not associated with tumor grade or stage. In about half the patients with pancreatic ductal adenocarcinoma tested,[15] lumican in the extracellular matrix around the tumor was associated with a reduction in metastatic recurrence after surgery and with a three-fold longer survival than patients without stromal lumican. As lumican can directly bind to and inhibit matrix metalloproteinase-14 (MMP14), lumican may limit tumor progression by preventing extracellular matrix collagen proteolysis by this enzyme.[16]

References

  1. ↑ Blochberger, T. C.; Vergnes, J. P.; Hempel, J.; Hassell, J. R. (1992-01-05). "cDNA to chick lumican (corneal keratan sulfate proteoglycan) reveals homology to the small interstitial proteoglycan gene family and expression in muscle and intestine". The Journal of Biological Chemistry 267 (1): 347–352. doi:10.1016/S0021-9258(18)48500-6. ISSN 0021-9258. PMID 1370446. 
  2. ↑ 2.0 2.1 "Entrez Gene: LUM lumican". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4060. 
  3. ↑ "Primary structure of human lumican (keratan sulfate proteoglycan) and localization of the gene (LUM) to chromosome 12q21.3-q22". Genomics 27 (3): 481–8. Jun 1995. doi:10.1006/geno.1995.1080. PMID 7558030. 
  4. ↑ "Proteoglycan form and function: A comprehensive nomenclature of proteoglycans". Matrix Biology 42: 11–55. Mar 2015. doi:10.1016/j.matbio.2015.02.003. PMID 25701227. 
  5. ↑ "Focus on molecules: lumican". Experimental Eye Research 82 (1): 3–4. Jan 2006. doi:10.1016/j.exer.2005.08.012. PMID 16213485. 
  6. ↑ "Proteodermatan and proteokeratan sulfate (decorin, lumican/fibromodulin) proteins are horseshoe shaped. Implications for their interactions with collagen". Biochemistry 35 (27): 8795–9. 1996. doi:10.1021/bi960773t. PMID 8688414. 
  7. ↑ "Functions of lumican and fibromodulin: lessons from knockout mice". Glycoconjugate Journal 19 (4–5): 287–93. 2002. doi:10.1023/A:1025348417078. PMID 12975607. 
  8. ↑ "Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican". The Journal of Cell Biology 141 (5): 1277–86. Jun 1998. doi:10.1083/jcb.141.5.1277. PMID 9606218. 
  9. ↑ "Lack of association between LUM rs3759223 polymorphism and high myopia". Optometry and Vision Science 91 (7): 707–12. Jul 2014. doi:10.1097/OPX.0000000000000302. PMID 24927138. 
  10. ↑ "Mouse models in tendon and ligament research". Progress in Heritable Soft Connective Tissue Diseases. Advances in Experimental Medicine and Biology. 802. 2014. pp. 201–30. doi:10.1007/978-94-007-7893-1_13. ISBN 978-94-007-7892-4. 
  11. ↑ "Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly". Journal of Molecular and Cellular Cardiology 84: 70–80. Apr 2015. doi:10.1016/j.yjmcc.2015.04.007. PMID 25886697. 
  12. ↑ "Focal experimental injury leads to widespread gene expression and histologic changes in equine flexor tendons". PLOS ONE 10 (4): e0122220. 2015. doi:10.1371/journal.pone.0122220. PMID 25837713. Bibcode: 2015PLoSO..1022220J. 
  13. ↑ "Small leucine rich proteoglycans are differently distributed in normal and pathological endometrium". In Vivo 29 (2): 217–22. 2015. PMID 25792648. 
  14. ↑ "Lumican is overexpressed in lung adenocarcinoma pleural effusions". PLOS ONE 10 (5): e0126458. 2015. doi:10.1371/journal.pone.0126458. PMID 25961303. Bibcode: 2015PLoSO..1026458C. 
  15. ↑ "Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery". Clinical Cancer Research 20 (24): 6529–40. Dec 2014. doi:10.1158/1078-0432.CCR-14-0970. PMID 25336691. 
  16. ↑ "Lumican: a new inhibitor of matrix metalloproteinase-14 activity". FEBS Letters 588 (23): 4319–24. Nov 2014. doi:10.1016/j.febslet.2014.09.040. PMID 25304424. 

Further reading



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