Cathepsin B Explained

Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis.^[1] In humans, cathepsin B is encoded by the CTSB gene.^{[2] [3]} Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.^{[4] [5] [6] [7]}

Structure

Gene

The CTSB gene is located at chromosome 8p22, consisting of 13 exons. The promoter of CTSB gene contains a GC-rich region including many SP1 sites, which is similar to housekeeping genes.^[8] At least five transcript variants encoding the same protein have been found for this gene.^[9]

Protein

Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acids with a signal peptide of 17 amino acids.^{[10] [11]} Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus, where cathepsin B is formed. Mature cathepsin B is composed of a heavy chain of 25-26 kDa and a light chain of 5kDa, which are linked by a dimer of disulfide.

Function

Cathepsin B may enhance the activity of other proteases, including matrix metalloproteinase, urokinase (serine protease urokinase plasminogen activator), and cathepsin D,^{[12] [13]} and thus it has an essential position for the proteolysis of extracellular matrix components, intercellular communication disruption, and reduced protease inhibitor expression.^[7]

Cells may become carcinogenic when cathepsin B is unregulated.^[14]

Potential in cancer

Cathepsin B has been proposed as a potentially effective biomarker for a variety of cancers.^{[12] [15]} Overexpression of cathepsin B is correlated with invasive and metastatic cancers.^[16]

Interactions

Cathepsin B has been shown to interact with:

• CTSD^[17]
• CSTA,^[18]
• CSTB,^{[19] [20]} and
• S100A10.^[21]

Cathepsin B is inhibited by:

• Nitroxoline^[22]
• CA-074^[23]

See also

• Cathepsins

Further reading

• Yan S, Sloane BF . Molecular regulation of human cathepsin B: implication in pathologies . Biological Chemistry . 384 . 6 . 845–54 . June 2003 . 12887051 . 10.1515/BC.2003.095 . 27472370 .

External links

• The MEROPS online database for peptidases and their inhibitors: C01.060

Notes and References

1. Sloane BF . Cathepsin B and cystatins: evidence for a role in cancer progression . Seminars in Cancer Biology . 1 . 2 . 137–52 . April 1990 . 2103490 .
2. Chan SJ, San Segundo B, McCormick MB, Steiner DF . Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs . Proceedings of the National Academy of Sciences of the United States of America . 83 . 20 . 7721–5 . October 1986 . 3463996 . 386793 . 10.1073/pnas.83.20.7721 . 1986PNAS...83.7721C . free .
3. Cao L, Taggart RT, Berquin IM, Moin K, Fong D, Sloane BF . Bonnie Sloane. Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene . Gene . 139 . 2 . 163–9 . February 1994 . 8112600 . 10.1016/0378-1119(94)90750-1 .
4. Tong B, Wan B, Wei Z, Wang T, Zhao P, Dou Y, Lv Z, Xia Y, Dai Y . Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis . Clinical and Experimental Immunology . 177 . 3 . 586–97 . September 2014 . 24749816 . 10.1111/cei.12357 . 4137842.
5. Lai WF, Chang CH, Tang Y, Bronson R, Tung CH . Early diagnosis of osteoarthritis using cathepsin B sensitive near-infrared fluorescent probes . Osteoarthritis and Cartilage . 12 . 3 . 239–44 . March 2004 . 14972341 . 10.1016/j.joca.2003.11.005 . free .
6. Ha SD, Ham B, Mogridge J, Saftig P, Lin S, Kim SO . Cathepsin B-mediated autophagy flux facilitates the anthrax toxin receptor 2-mediated delivery of anthrax lethal factor into the cytoplasm . The Journal of Biological Chemistry . 285 . 3 . 2120–9 . January 2010 . 19858192 . 10.1074/jbc.M109.065813 . 2804368. free .
7. Yang WE, Ho CC, Yang SF, Lin SH, Yeh KT, Lin CW, Chen MK . Cathepsin B Expression and the Correlation with Clinical Aspects of Oral Squamous Cell Carcinoma . PLOS ONE . 11 . 3 . e0152165 . 2016 . 27031837 . 10.1371/journal.pone.0152165 . 4816521. 2016PLoSO..1152165Y . free .
8. Qian F, Frankfater A, Chan SJ, Steiner DF . The structure of the mouse cathepsin B gene and its putative promoter . DNA and Cell Biology . 10 . 3 . 159–68 . April 1991 . 2012677 . 10.1089/dna.1991.10.159 .
9. Web site: Entrez Gene: CTSB cathepsin B.
10. Kirschke H, Barrett AJ, Rawlings ND . Proteinases 1: lysosomal cysteine proteinases . Protein Profile . 2 . 14 . 1581–643 . 1995 . 8771190 .
11. Mort JS, Buttle DJ . Cathepsin B . The International Journal of Biochemistry & Cell Biology . 29 . 5 . 715–20 . May 1997 . 9251238 . 10.1016/s1357-2725(96)00152-5. 37767552 .
12. Alapati K, Kesanakurti D, Rao JS, Dasari VR . uPAR and cathepsin B-mediated compartmentalization of JNK regulates the migration of glioma-initiating cells . Stem Cell Research . 12 . 3 . 716–29 . May 2014 . 24699410 . 10.1016/j.scr.2014.02.008 . 4061617.
13. Vigneswaran N, Zhao W, Dassanayake A, Muller S, Miller DM, Zacharias W . Variable expression of cathepsin B and D correlates with highly invasive and metastatic phenotype of oral cancer . Human Pathology . 31 . 8 . 931–7 . August 2000 . 10987253 . 10.1053/hupa.2000.9035 .
14. Aggarwal . Neha . Sloane . Bonnie F. . June 2014 . Cathepsin B: Multiple roles in cancer . Proteomics. Clinical Applications . 8 . 5–6 . 427–437 . 10.1002/prca.201300105 . 1862-8346 . 4205946 . 24677670.
15. Bian B, Mongrain S, Cagnol S, Langlois MJ, Boulanger J, Bernatchez G, Carrier JC, Boudreau F, Rivard N . Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis . Molecular Carcinogenesis . 55 . 5 . 671–87 . May 2016 . 25808857 . 10.1002/mc.22312 . 4832390.
16. Ruan J, Zheng H, Rong X, Rong X, Zhang J, Fang W, Zhao P, Luo R . Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients . Molecular Cancer . 15 . 17 . 20 February 2016 . 26896959 . 10.1186/s12943-016-0503-9 . 4761221 . free .
17. van der Stappen JW, Williams AC, Maciewicz RA, Paraskeva C . Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D . International Journal of Cancer . 67 . 4 . 547–54 . August 1996 . 8759615 . 10.1002/(SICI)1097-0215(19960807)67:4<547::AID-IJC14>3.0.CO;2-4 . free .
18. Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I . The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L . Biochemistry . 37 . 20 . 7551–60 . May 1998 . 9585570 . 10.1021/bi980026r .
19. Pavlova A, Björk I . Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases . Biochemistry . 42 . 38 . 11326–33 . September 2003 . 14503883 . 10.1021/bi030119v .
20. Pol E, Björk I . Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases . Protein Science . 10 . 9 . 1729–38 . September 2001 . 11514663 . 2253190 . 10.1110/ps.11901 .
21. Mai J, Finley RL, Waisman DM, Sloane BF . Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells . The Journal of Biological Chemistry . 275 . 17 . 12806–12 . April 2000 . 10777578 . 10.1074/jbc.275.17.12806 . free .
22. Hurley EA, Thorley-Lawson DA . B cell activation and the establishment of Epstein-Barr virus latency . The Journal of Experimental Medicine . 168 . 6 . 2059–75 . December 1988 . 2848918 . 10.1084/jem.168.6.2059 . 2189139.
23. Murata M, Miyashita S, Yokoo C, Tamai M, Hanada K, Hatayama K, Towatari T, Nikawa T, Katunuma N . Novel epoxysuccinyl peptides. Selective inhibitors of cathepsin B, in vitro . FEBS Letters . 280 . 2 . 311–15 . March 1991 . 2013328 . 10.1016/0014-5793(91)80318-w . 46523390 . free .