Lumican Explained

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]

Further reading

• Grover J, Chen XN, Korenberg JR, Roughley PJ . The human lumican gene. Organization, chromosomal location, and expression in articular cartilage . The Journal of Biological Chemistry . 270 . 37 . 21942–9 . Sep 1995 . 7665616 . 10.1074/jbc.270.37.21942 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Rada JA, Cornuet PK, Hassell JR . Regulation of corneal collagen fibrillogenesis in vitro by corneal proteoglycan (lumican and decorin) core proteins . Experimental Eye Research . 56 . 6 . 635–48 . Jun 1993 . 8595806 . 10.1006/exer.1993.1081 .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–828 . Sep 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Matsushima N, Ohyanagi T, Tanaka T, Kretsinger RH . Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin . Proteins . 38 . 2 . 210–25 . Feb 2000 . 10656267 . 10.1002/(SICI)1097-0134(20000201)38:2<210::AID-PROT9>3.0.CO;2-1 . 39643243 .
• Svensson L, Närlid I, Oldberg A . Fibromodulin and lumican bind to the same region on collagen type I fibrils . FEBS Letters . 470 . 2 . 178–82 . Mar 2000 . 10734230 . 10.1016/S0014-5793(00)01314-4 . 46539089 .
• Pellegata NS, Dieguez-Lucena JL, Joensuu T, Lau S, Montgomery KT, Krahe R, Kivelä T, Kucherlapati R, Forsius H, de la Chapelle A . Mutations in KERA, encoding keratocan, cause cornea plana . Nature Genetics . 25 . 1 . 91–5 . May 2000 . 10802664 . 10.1038/75664 . 8837115 .
• Neame PJ, Kay CJ, McQuillan DJ, Beales MP, Hassell JR . Independent modulation of collagen fibrillogenesis by decorin and lumican . Cellular and Molecular Life Sciences . 57 . 5 . 859–63 . May 2000 . 10892350 . 10.1007/s000180050048 . 21998935 . free . 11146782 .
• Grover J, Liu CY, Kao WW, Roughley PJ . Analysis of the human lumican gene promoter . The Journal of Biological Chemistry . 275 . 52 . 40967–73 . Dec 2000 . 11016924 . 10.1074/jbc.M004134200 . free .
• Naito Z, Ishiwata T, Kurban G, Teduka K, Kawamoto Y, Kawahara K, Sugisaki Y . Expression and accumulation of lumican protein in uterine cervical cancer cells at the periphery of cancer nests . International Journal of Oncology . 20 . 5 . 943–8 . May 2002 . 11956587 . 10.3892/ijo.20.5.943 .
• Lu YP, Ishiwata T, Kawahara K, Watanabe M, Naito Z, Moriyama Y, Sugisaki Y, Asano G . Expression of lumican in human colorectal cancer cells . Pathology International . 52 . 8 . 519–26 . Aug 2002 . 12366811 . 10.1046/j.1440-1827.2002.01384.x . 38324942 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–903 . Dec 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A . The human plasma proteome: a nonredundant list developed by combination of four separate sources . Molecular & Cellular Proteomics . 3 . 4 . 311–26 . Apr 2004 . 14718574 . 10.1074/mcp.M300127-MCP200 . free .
• Bunkenborg J, Pilch BJ, Podtelejnikov AV, Wiśniewski JR . Screening for N-glycosylated proteins by liquid chromatography mass spectrometry . Proteomics . 4 . 2 . 454–65 . Feb 2004 . 14760718 . 10.1002/pmic.200300556 . 29261009 .
• Botella LM, Sanz-Rodriguez F, Sanchez-Elsner T, Langa C, Ramirez JR, Vary C, Roughley PJ, Bernabeu C . Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression . Matrix Biology . 22 . 7 . 561–72 . Jan 2004 . 14996436 . 10.1016/j.matbio.2003.11.006 .
• Vuillermoz B, Khoruzhenko A, D'Onofrio MF, Ramont L, Venteo L, Perreau C, Antonicelli F, Maquart FX, Wegrowski Y . The small leucine-rich proteoglycan lumican inhibits melanoma progression . Experimental Cell Research . 296 . 2 . 294–306 . Jun 2004 . 15149859 . 10.1016/j.yexcr.2004.02.005 .
• Köninger J, Giese T, di Mola FF, Wente MN, Esposito I, Bachem MG, Giese NA, Büchler MW, Friess H . Pancreatic tumor cells influence the composition of the extracellular matrix . Biochemical and Biophysical Research Communications . 322 . 3 . 943–9 . Sep 2004 . 15336555 . 10.1016/j.bbrc.2004.08.008 .
• Li Y, Aoki T, Mori Y, Ahmad M, Miyamori H, Takino T, Sato H . Cleavage of lumican by membrane-type matrix metalloproteinase-1 abrogates this proteoglycan-mediated suppression of tumor cell colony formation in soft agar . Cancer Research . 64 . 19 . 7058–64 . Oct 2004 . 15466200 . 10.1158/0008-5472.CAN-04-1038 . free . 2297/15892 . free .

Notes and 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. 10.1016/S0021-9258(18)48500-6. 0021-9258. 1370446. free.
2. Web site: Entrez Gene: LUM lumican.
3. Chakravarti S, Stallings RL, SundarRaj N, Cornuet PK, Hassell JR . 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 . 7558030 . 10.1006/geno.1995.1080 .
4. Iozzo RV, Schaefer L . Proteoglycan form and function: A comprehensive nomenclature of proteoglycans . Matrix Biology . 42 . 11–55 . Mar 2015 . 25701227 . 10.1016/j.matbio.2015.02.003 . 4859157.
5. Kao WW, Funderburgh JL, Xia Y, Liu CY, Conrad GW . Focus on molecules: lumican . Experimental Eye Research . 82 . 1 . 3–4 . Jan 2006 . 16213485 . 2876311 . 10.1016/j.exer.2005.08.012 .
6. Scott JE . Proteodermatan and proteokeratan sulfate (decorin, lumican/fibromodulin) proteins are horseshoe shaped. Implications for their interactions with collagen . Biochemistry . 35 . 27 . 8795–9 . 1996 . 8688414 . 10.1021/bi960773t .
7. Chakravarti S . Functions of lumican and fibromodulin: lessons from knockout mice . Glycoconjugate Journal . 19 . 4–5 . 287–93 . 2002 . 12975607 . 10.1023/A:1025348417078 . 3636866 .
8. Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H . 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 . 9606218 . 2137175 . 10.1083/jcb.141.5.1277.
9. Li M, Zhai L, Zeng S, Peng Q, Wang J, Deng Y, Xie L, He Y, Li T . Lack of association between LUM rs3759223 polymorphism and high myopia . Optometry and Vision Science . 91 . 7 . 707–12 . Jul 2014 . 24927138 . 10.1097/OPX.0000000000000302 . 27647081 .
10. Book: Mienaltowski MJ, Birk DE . Mouse models in tendon and ligament research . 802 . 201–30 . 2014 . 24443029 . 10.1007/978-94-007-7893-1_13 . Advances in Experimental Medicine and Biology . 978-94-007-7892-4 . Progress in Heritable Soft Connective Tissue Diseases .
11. Dupuis LE, Berger MG, Feldman S, Doucette L, Fowlkes V, Chakravarti S, Thibaudeau S, Alcala NE, Bradshaw AD, Kern CB . Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly . Journal of Molecular and Cellular Cardiology . 84 . 70–80 . Apr 2015 . 25886697 . 10.1016/j.yjmcc.2015.04.007 . 4468017.
12. Jacobson E, Dart AJ, Mondori T, Horadogoda N, Jeffcott LB, Little CB, Smith MM . Focal experimental injury leads to widespread gene expression and histologic changes in equine flexor tendons . PLOS ONE . 10 . 4 . e0122220 . 2015 . 25837713 . 4383631 . 10.1371/journal.pone.0122220 . 2015PLoSO..1022220J . free .
13. Lucariello A, Trabucco E, Boccia O, Perna A, Sellitto C, Castaldi MA, De Falco M, De Luca A, Cobellis L . Small leucine rich proteoglycans are differently distributed in normal and pathological endometrium . In Vivo . 29 . 2 . 217–22 . 2015 . 25792648 .
14. Cappellesso R, Millioni R, Arrigoni G, Simonato F, Caroccia B, Iori E, Guzzardo V, Ventura L, Tessari P, Fassina A . Lumican is overexpressed in lung adenocarcinoma pleural effusions . PLOS ONE . 10 . 5 . e0126458 . 2015 . 25961303 . 4427354 . 10.1371/journal.pone.0126458 . 2015PLoSO..1026458C . free .
15. 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 . Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery . Clinical Cancer Research . 20 . 24 . 6529–40 . Dec 2014 . 25336691 . 4268437 . 10.1158/1078-0432.CCR-14-0970 .
16. Pietraszek K, Chatron-Colliet A, Brézillon S, Perreau C, Jakubiak-Augustyn A, Krotkiewski H, Maquart FX, Wegrowski Y . Lumican: a new inhibitor of matrix metalloproteinase-14 activity . FEBS Letters . 588 . 23 . 4319–24 . Nov 2014 . 25304424 . 10.1016/j.febslet.2014.09.040 . 36035579 . free .