CHI3L1

Chitinase 3-like 1 (cartilage glycoprotein-39)
PDB rendering based on 1hjv.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1HJV​, 1HJW​, 1HJX​, 1LA7​, 1NWR​, 1NWS​, 1NWT​, 1NWU​
Identifiers
Symbols	CHI3L1 ; ASRT7; CGP-39; GP-39; GP39; HC-gp39; HCGP-3P; YKL-40; YKL40; YYL-40; hCGP-39
External IDs	OMIM: 601525 MGI: 1340899 HomoloGene: 55569 GeneCards: CHI3L1 Gene
Gene ontology Molecular function • chitinase activity • extracellular matrix structural constituent • chitin binding • carbohydrate binding Cellular component • extracellular region • proteinaceous extracellular matrix • extracellular space • cytoplasm • endoplasmic reticulum • perinuclear region of cytoplasm • extracellular exosome Biological process • carbohydrate metabolic process • chitin catabolic process • apoptotic process • inflammatory response • activation of NF-kappaB-inducing kinase activity • response to mechanical stimulus • positive regulation of peptidyl-threonine phosphorylation • lung development • response to tumor necrosis factor • positive regulation of angiogenesis • cartilage development • positive regulation of protein kinase B signaling • positive regulation of ERK1 and ERK2 cascade • response to interleukin-1 • response to interleukin-6 • cellular response to interleukin-1 • cellular response to tumor necrosis factor • interleukin-8 secretion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1116	12654
Ensembl	ENSG00000133048	ENSMUSG00000064246
UniProt	P36222	Q61362
RefSeq (mRNA)	NM_001276	NM_007695
RefSeq (protein)	NP_001267	NP_031721
Location (UCSC)	Chr 1: 203.18 – 203.19 Mb	Chr 1: 134.18 – 134.19 Mb
PubMed search

Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene.^[1][2][3] The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is secreted by various cell-types including macrophages, chondrocytes, and some types of cancer cells. YKL-40 lacks chitinase activity due to mutations within the active site (conserved sequence: DXXDXDXE ; YKL-40 sequence: DGLDLAWL). The exact physiological role of YKL-40 is not known, but it has been implicated in development, inflammatory disease (such as asthma,^[4] and cancer progression).

Function

Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling.^[3]

Regulation and mechanism

YKL-40 has been linked to activation of the AKT pro-survival (anti-apoptotic) signaling pathway.^[5]

YKL-40 is a migration factor for primary astrocytes and its expression is controlled by NFI-X3, STAT3, and AP-1.^[6]

Role in cancer

YKL-40 is a Th2 promoting cytokine that is present at high levels in the tumor micro-environment and in the serum of cancer patients.^[7][8] Elevated levels of YKL-40 correlate strongly with stage and outcome of various types of cancer, which establish YKL-40 as a biomarker of disease severity.^[9] Targeting YKL-40 with neutralizing antibodies has been proven effective as a treatment in animal models of glioblastoma multiforme.^[10] YKL-40 is able to promote angiogenesis through VEGF-dependent and independent pathways.^[5]

YKL-40 also enhances tumor survival in response to gamma-irradiation.^[5]

References

1. Hakala BE, White C, Recklies AD (Jan 1994). "Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family". J Biol Chem 268 (34): 25803–10. PMID 8245017.
2. Rehli M, Krause SW, Andreesen R (Sep 1997). "Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation". Genomics 43 (2): 221–5. doi:10.1006/geno.1997.4778. PMID 9244440.
3. "Entrez Gene: CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39)".
4. Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, Radford S, Parry RR, Heinzmann A, Deichmann KA, Lester LA, Gern JE, Lemanske RF, Nicolae DL, Elias JA, Chupp GL (April 2008). "Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function". N. Engl. J. Med. 358 (16): 1682–91. doi:10.1056/NEJMoa0708801. PMC 2629486. PMID 18403759.
5. Francescone RA, Scully S, Faibish M, Taylor SL, Oh D, Moral L, Yan W, Bentley B, Shao R (April 2011). "Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma". J. Biol. Chem. 286 (17): 15332–43. doi:10.1074/jbc.M110.212514. PMC 3083166. PMID 21385870.
6. Singh SK, Bhardwaj R, Wilczynska KM, Dumur CI, Kordula T (November 2011). "A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40". J. Biol. Chem. 286 (46): 39893–903. doi:10.1074/jbc.M111.257451. PMC 3220556. PMID 21953450.
7. Høgdall EV, Ringsholt M, Høgdall CK, Christensen IJ, Johansen JS, Kjaer SK, Blaakaer J, Ostenfeld-Møller L, Price PA, Christensen LH (2009). "YKL-40 tissue expression and plasma levels in patients with ovarian cancer". BMC Cancer 9: 8. doi:10.1186/1471-2407-9-8. PMC 2645422. PMID 19134206.
8. Bernardi D, Padoan A, Ballin A, Sartori M, Manara R, Scienza R, Plebani M, Della Puppa A (April 2012). "Serum YKL-40 following resection for cerebral glioblastoma". J. Neurooncol. 107 (2): 299–305. doi:10.1007/s11060-011-0762-7. PMID 22102082.
9. Johansen JS, Christensen IJ, Riisbro R, Greenall M, Han C, Price PA, Smith K, Brünner N, Harris AL (July 2003). "High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival". Breast Cancer Res. Treat. 80 (1): 15–21. doi:10.1023/A:1024431000710. PMID 12889595.
10. Faibish M, Francescone R, Bentley B, Yan W, Shao R (May 2011). "A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers". Mol. Cancer Ther. 10 (5): 742–51. doi:10.1158/1535-7163.MCT-10-0868. PMC 3091949. PMID 21357475.

Further reading

• Rathcke CN, Vestergaard H (2007). "YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis.". Inflamm. Res. 55 (6): 221–7. doi:10.1007/s00011-006-0076-y. PMID 16955240.
• Nyirkos P, Golds EE (1990). "Human synovial cells secrete a 39 kDa protein similar to a bovine mammary protein expressed during the non-lactating period.". Biochem. J. 269 (1): 265–8. PMC 1131563. PMID 2375755.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K; et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Kirkpatrick RB, Emery JG, Connor JR; et al. (1998). "Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages.". Exp. Cell Res. 237 (1): 46–54. doi:10.1006/excr.1997.3764. PMID 9417865.
• Renkema GH, Boot RG, Au FL; et al. (1998). "Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages.". Eur. J. Biochem. 251 (1-2): 504–9. doi:10.1046/j.1432-1327.1998.2510504.x. PMID 9492324.
• Johansen JS, Stoltenberg M, Hansen M; et al. (1999). "Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity.". Rheumatology (Oxford) 38 (7): 618–26. doi:10.1093/rheumatology/38.7.618. PMID 10461474.
• Nordenbaek C, Johansen JS, Junker P; et al. (1999). "YKL-40, a matrix protein of specific granules in neutrophils, is elevated in serum of patients with community-acquired pneumonia requiring hospitalization.". J. Infect. Dis. 180 (5): 1722–6. doi:10.1086/315050. PMID 10515841.
• Connor JR, Dodds RA, Emery JG; et al. (2000). "Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization.". Osteoarthr. Cartil. 8 (2): 87–95. doi:10.1053/joca.1999.0276. PMID 10772238.
• Østergaard C, Johansen JS, Benfield T; et al. (2002). "YKL-40 is elevated in cerebrospinal fluid from patients with purulent meningitis.". Clin. Diagn. Lab. Immunol. 9 (3): 598–604. doi:10.1128/CDLI.9.3.598-604.2002. PMC 119997. PMID 11986266.
• Kronborg G, Ostergaard C, Weis N; et al. (2003). "Serum level of YKL-40 is elevated in patients with Streptococcus pneumoniae bacteremia and is associated with the outcome of the disease.". Scand. J. Infect. Dis. 34 (5): 323–6. doi:10.1080/00365540110080233. PMID 12069012.
• Recklies AD, White C, Ling H (2002). "The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways.". Biochem. J. 365 (Pt 1): 119–26. doi:10.1042/BJ20020075. PMC 1222662. PMID 12071845.
• Cintin C, Johansen JS, Christensen IJ; et al. (2002). "High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival.". Cancer 95 (2): 267–74. doi:10.1002/cncr.10644. PMID 12124825.
• Steck E, Breit S, Breusch SJ; et al. (2003). "Enhanced expression of the human chitinase 3-like 2 gene (YKL-39) but not chitinase 3-like 1 gene (YKL-40) in osteoarthritic cartilage.". Biochem. Biophys. Res. Commun. 299 (1): 109–15. doi:10.1016/S0006-291X(02)02585-8. PMID 12435396.
• Strausberg RL, Feingold EA, Grouse LH; et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Steenbakkers PG, Baeten D, Rovers E; et al. (2003). "Localization of MHC class II/human cartilage glycoprotein-39 complexes in synovia of rheumatoid arthritis patients using complex-specific monoclonal antibodies.". J. Immunol. 170 (11): 5719–27. doi:10.4049/jimmunol.170.11.5719. PMID 12759455.
• Houston DR, Recklies AD, Krupa JC, van Aalten DM (2003). "Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes.". J. Biol. Chem. 278 (32): 30206–12. doi:10.1074/jbc.M303371200. PMID 12775711.
• Nishikawa KC, Millis AJ (2003). "gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells.". Exp. Cell Res. 287 (1): 79–87. doi:10.1016/S0014-4827(03)00069-7. PMID 12799184.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.