Cathepsin K

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.

CTSK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MEM, 3KWB, 3KX1, 4X6J, 1AYW, 3KW9, 1YT7, 1AU2, 4X6H, 1Q6K, 1YK7, 1ATK, 3C9E, 1AYV, 1BGO, 4N8W, 7PCK, 4DMX, 4X6I, 1NL6, 1TU6, 3O0U, 1AU4, 3OVZ, 3KWZ, 2ATO, 3O1G, 1AU0, 1BY8, 1SNK, 2AUZ, 4DMY, 4N79, 1AYU, 1U9X, 1YK8, 1AU3, 1U9V, 2BDL, 1VSN, 1U9W, 2AUX, 2R6N, 3H7D, 1NLJ, 5J94, 4YVA, 4YV8
Identifiers
Aliases	CTSK, CTS02, CTSO, CTSO1, CTSO2, PKND, PYCD, cathepsin K
External IDs	OMIM: 601105; MGI: 107823; HomoloGene: 68053; GeneCards: CTSK; OMA:CTSK - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q21.3 Start 150,794,880 bp End 150,809,577 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3 F2.1|3 40.74 cM Start 95,406,567 bp End 95,416,673 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in periodontal fiber skin of hip stromal cell of endometrium gallbladder tibia gastric mucosa skin of thigh canal of the cervix decidua ectocervix Top expressed in body of femur calvaria decidua tibiofemoral joint ankle skin of external ear vestibular sensory epithelium stroma of bone marrow gastrula ankle joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function fibronectin binding cysteine-type peptidase activity collagen binding peptidase activity protein binding cysteine-type endopeptidase activity hydrolase activity proteoglycan binding serine-type endopeptidase activity Cellular component cytoplasm extracellular region endolysosome lumen lysosome extracellular space nucleoplasm intracellular membrane-bounded organelle lysosomal lumen Biological process intramembranous ossification positive regulation of protein targeting to mitochondrion extracellular matrix disassembly bone resorption proteolysis toll-like receptor signaling pathway regulation of autophagy of mitochondrion collagen catabolic process proteolysis involved in cellular protein catabolic process regulation of keratinocyte differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1513 13038 Ensembl ENSG00000143387 ENSMUSG00000028111 UniProt P43235 P55097 RefSeq (mRNA) NM_000396 NM_007802 RefSeq (protein) NP_000387 NP_031828 Location (UCSC) Chr 1: 150.79 – 150.81 Mb Chr 3: 95.41 – 95.42 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene is a cysteine cathepsin, a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is expressed predominantly in osteoclasts.

Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme's ability to catabolize elastin, collagen, and gelatin allows it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors show great potential in the treatment of osteoporosis. Cathepsin K is degraded by Cathepsin S, in a process referred to as Controlled Cathepsin Cannibalism.

Cathepsin K expression is stimulated by inflammatory cytokines that are released after tissue injury.

Clinical significance

Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. Cathepsin K has also been found to be over-expressed in glioblastoma.

That the expression of cathepsin K is characteristic for some cancers and not others has been documented. Cathepsin K antibodies are marketed for research into expression of this enzyme by various cells.

Merck had a cathepsin K inhibitor, odanacatib, in Phase III clinical trials for osteoporosis. In September, 2016, Merck announced they were discontinuing development of odanacatib after their own assessment of adverse events and an independent assessment showed increased risk of stroke. Other cathepsin K inhibitors are in various stages of development. Medivir has a cathepsin K inhibitor, MIV-711 (L-006235), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.

Further reading

• Motyckova G, Fisher DE (2003). "Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease". Current Molecular Medicine. 2 (5): 407–21. doi:10.2174/1566524023362401. PMID 12125807.
• Troen BR (2006). "The regulation of cathepsin K gene expression". Annals of the New York Academy of Sciences. 1068 (1): 165–72. Bibcode:2006NYASA1068..165T. doi:10.1196/annals.1346.018. PMID 16831915. S2CID 8117602.
• Del Nery E, Chagas JR, Juliano MA, et al. (1996). "Evaluation of the extent of the binding site in human tissue kallikrein by synthetic substrates with sequences of human kininogen fragments". The Biochemical Journal. 312 (1): 233–8. doi:10.1042/bj3120233. PMC 1136249. PMID 7492318.
• Brömme D, Okamoto K (1995). "Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution". Biological Chemistry Hoppe-Seyler. 376 (6): 379–84. doi:10.1515/bchm3.1995.376.6.379. PMID 7576232.
• Gelb BD, Edelson JG, Desnick RJ (1995). "Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping". Nature Genetics. 10 (2): 235–7. doi:10.1038/ng0695-235. PMID 7663521. S2CID 24297764.
• Polymeropoulos MH, Ortiz De Luna RI, Ide SE, et al. (1995). "The gene for pycnodysostosis maps to human chromosome 1cen-q21". Nature Genetics. 10 (2): 238–9. doi:10.1038/ng0695-238. PMID 7663522. S2CID 11723845.
• Shi GP, Chapman HA, Bhairi SM, et al. (1995). "Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2" (PDF). FEBS Letters. 357 (2): 129–34. doi:10.1016/0014-5793(94)01349-6. PMID 7805878. S2CID 28099876.
• Inaoka T, Bilbe G, Ishibashi O, et al. (1995). "Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone". Biochemical and Biophysical Research Communications. 206 (1): 89–96. doi:10.1006/bbrc.1995.1013. PMID 7818555.
• Velasco G, Ferrando AA, Puente XS, et al. (1994). "Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues". The Journal of Biological Chemistry. 269 (43): 27136–42. doi:10.1016/S0021-9258(18)47135-9. PMID 7929457.
• Li YP, Alexander M, Wucherpfennig AL, et al. (1996). "Cloning and complete coding sequence of a novel human cathepsin expressed in giant cells of osteoclastomas". Journal of Bone and Mineral Research. 10 (8): 1197–202. doi:10.1002/jbmr.5650100809. PMID 8585423. S2CID 41832979.
• Bossard MJ, Tomaszek TA, Thompson SK, et al. (1996). "Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification". Journal of Biological Chemistry. 271 (21): 12517–24. doi:10.1074/jbc.271.21.12517. PMID 8647860.
• Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996). "Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency". Science. 273 (5279): 1236–8. Bibcode:1996Sci...273.1236G. doi:10.1126/science.273.5279.1236. PMID 8703060. S2CID 7188076.
• Johnson MR, Polymeropoulos MH, Vos HL, et al. (1997). "A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis". Genome Research. 6 (11): 1050–5. doi:10.1101/gr.6.11.1050. PMID 8938428.
• Littlewood-Evans A, Kokubo T, Ishibashi O, et al. (1997). "Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry". Bone. 20 (2): 81–6. doi:10.1016/S8756-3282(96)00351-1. PMID 9028530.
• McGrath ME, Klaus JL, Barnes MG, Brömme D (1997). "Crystal structure of human cathepsin K complexed with a potent inhibitor". Nature Structural Biology. 4 (2): 105–9. doi:10.1038/nsb0297-105. PMID 9033587. S2CID 22175354.
• Rood JA, Van Horn S, Drake FH, et al. (1997). "Genomic organization and chromosome localization of the human cathepsin K gene (CTSK)". Genomics. 41 (2): 169–76. doi:10.1006/geno.1997.4614. PMID 9143491.
• Gelb BD, Shi GP, Heller M, et al. (1997). "Structure and chromosomal assignment of the human cathepsin K gene". Genomics. 41 (2): 258–62. doi:10.1006/geno.1997.4631. PMID 9143502.
• Gomes RA, Juliano L, Chagas JR, Hial V (1997). "Characterization of kininogenase activity of an acidic proteinase isolated from human kidney". Canadian Journal of Physiology and Pharmacology. 75 (6): 757–61. doi:10.1139/cjpp-75-6-757. PMID 9276160.
• Thompson SK, Halbert SM, Bossard MJ, et al. (1998). "Design of potent and selective human cathepsin K inhibitors that span the active site". Proceedings of the National Academy of Sciences. 94 (26): 14249–54. doi:10.1073/pnas.94.26.14249. PMC 24926. PMID 9405598.
• Gelb BD, Willner JP, Dunn TM, et al. (1998). "Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis". The American Journal of Human Genetics. 62 (4): 848–54. doi:10.1086/301795. PMC 1377035. PMID 9529353.

Additional images

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  Osteoclast

External links

• The MEROPS online database for peptidases and their inhibitors: C01.036
• Cathepsin+K at the U.S. National Library of Medicine Medical Subject Headings (MeSH)