Lumican

Lumican,[5] also known as LUM, is an extracellular matrix protein that, in humans, is encoded by the LUM gene on chromosome 12.[6][7]

LUM
Identifiers
AliasesLUM, LDC, SLRR2D, lumican
External IDsOMIM: 600616 MGI: 109347 HomoloGene: 37614 GeneCards: LUM
Orthologs
SpeciesHumanMouse
Entrez

4060

17022

Ensembl

ENSG00000139329

ENSMUSG00000036446

UniProt

P51884

P51885

RefSeq (mRNA)

NM_002345

NM_008524

RefSeq (protein)

NP_002336

NP_032550

Location (UCSC)Chr 12: 91.1 – 91.11 MbChr 10: 97.4 – 97.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8]

Like the other SLRPs, lumican has a molecular weight of about 40 kiloDaltons and has four major intramolecular domains:[9]

  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.[10]

Function

Lumican is a major keratan sulfate proteoglycan of the cornea but is ubiquitously distributed in most mesenchymal tissues throughout the body.[11] Lumican is involved in collagen fibril organization and circumferential growth, corneal transparency, and epithelial cell migration and tissue repair.[6] 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.[12] 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.[13]

Lum knockout mice also have abnormal collagen in their heart tissue, with fewer and thicker fibrils.[14] 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.[15] Along with other extracellular matrix components, lumican expression was increased in equine flexor tendons six weeks after an injury.[16]

Lumican is present in the extracellular matrix of uteral tissues in fertile women.[17] 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.[18] 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,[19] 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.[20]

References
  1. GRCh38: Ensembl release 89: ENSG00000139329 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000036446 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. "Entrez Gene: LUM lumican".
  7. Chakravarti S, Stallings RL, SundarRaj N, Cornuet PK, Hassell JR (Jun 1995). "Primary structure of human lumican (keratan sulfate proteoglycan) and localization of the gene (LUM) to chromosome 12q21.3-q22". Genomics. 27 (3): 481–8. doi:10.1006/geno.1995.1080. PMID 7558030.
  8. Iozzo RV, Schaefer L (Mar 2015). "Proteoglycan form and function: A comprehensive nomenclature of proteoglycans". Matrix Biology. 42: 11–55. doi:10.1016/j.matbio.2015.02.003. PMC 4859157. PMID 25701227.
  9. Kao WW, Funderburgh JL, Xia Y, Liu CY, Conrad GW (Jan 2006). "Focus on molecules: lumican". Experimental Eye Research. 82 (1): 3–4. doi:10.1016/j.exer.2005.08.012. PMC 2876311. PMID 16213485.
  10. Scott JE (1996). "Proteodermatan and proteokeratan sulfate (decorin, lumican/fibromodulin) proteins are horseshoe shaped. Implications for their interactions with collagen". Biochemistry. 35 (27): 8795–9. doi:10.1021/bi960773t. PMID 8688414.
  11. Chakravarti S (2002). "Functions of lumican and fibromodulin: lessons from knockout mice". Glycoconjugate Journal. 19 (4–5): 287–93. doi:10.1023/A:1025348417078. PMID 12975607. S2CID 3636866.
  12. Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H (Jun 1998). "Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican". The Journal of Cell Biology. 141 (5): 1277–86. doi:10.1083/jcb.141.5.1277. PMC 2137175. PMID 9606218.
  13. Li M, Zhai L, Zeng S, Peng Q, Wang J, Deng Y, Xie L, He Y, Li T (Jul 2014). "Lack of association between LUM rs3759223 polymorphism and high myopia". Optometry and Vision Science. 91 (7): 707–12. doi:10.1097/OPX.0000000000000302. PMID 24927138. S2CID 27647081.
  14. Mienaltowski MJ, Birk DE (2014). "Mouse models in tendon and ligament research". Progress in Heritable Soft Connective Tissue Diseases. Advances in Experimental Medicine and Biology. Vol. 802. pp. 201–30. doi:10.1007/978-94-007-7893-1_13. ISBN 978-94-007-7892-4. PMID 24443029.
  15. Dupuis LE, Berger MG, Feldman S, Doucette L, Fowlkes V, Chakravarti S, Thibaudeau S, Alcala NE, Bradshaw AD, Kern CB (Apr 2015). "Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly". Journal of Molecular and Cellular Cardiology. 84: 70–80. doi:10.1016/j.yjmcc.2015.04.007. PMC 4468017. PMID 25886697.
  16. Jacobson E, Dart AJ, Mondori T, Horadogoda N, Jeffcott LB, Little CB, Smith MM (2015). "Focal experimental injury leads to widespread gene expression and histologic changes in equine flexor tendons". PLOS ONE. 10 (4): e0122220. Bibcode:2015PLoSO..1022220J. doi:10.1371/journal.pone.0122220. PMC 4383631. PMID 25837713.
  17. Lucariello A, Trabucco E, Boccia O, Perna A, Sellitto C, Castaldi MA, De Falco M, De Luca A, Cobellis L (2015). "Small leucine rich proteoglycans are differently distributed in normal and pathological endometrium". In Vivo. 29 (2): 217–22. PMID 25792648.
  18. Cappellesso R, Millioni R, Arrigoni G, Simonato F, Caroccia B, Iori E, Guzzardo V, Ventura L, Tessari P, Fassina A (2015). "Lumican is overexpressed in lung adenocarcinoma pleural effusions". PLOS ONE. 10 (5): e0126458. Bibcode:2015PLoSO..1026458C. doi:10.1371/journal.pone.0126458. PMC 4427354. PMID 25961303.
  19. Li X, Truty MA, Kang Y, Chopin-Laly X, Zhang R, Roife D, Chatterjee D, Lin E, Thomas RM, Wang H, Katz MH, Fleming JB (Dec 2014). "Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery". Clinical Cancer Research. 20 (24): 6529–40. doi:10.1158/1078-0432.CCR-14-0970. PMC 4268437. PMID 25336691.
  20. Pietraszek K, Chatron-Colliet A, Brézillon S, Perreau C, Jakubiak-Augustyn A, Krotkiewski H, Maquart FX, Wegrowski Y (Nov 2014). "Lumican: a new inhibitor of matrix metalloproteinase-14 activity". FEBS Letters. 588 (23): 4319–24. doi:10.1016/j.febslet.2014.09.040. PMID 25304424. S2CID 36035579.

Further reading
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