Disease relevance of CTSL2

• Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis [1].
• Expression analysis of cathepsin L2 in human tumors revealed a widespread expression in colorectal and breast carcinomas but not in normal colon or mammary gland or in peritumoral tissues [2].
• The cDNA encoding the mature cathepsin L2 was expressed in Escherichia coli, and after purification, the recombinant protein was able to degrade the synthetic peptide benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin, which is commonly used as a substrate for cysteine proteinases [2].
• Cathepsin L2, a novel human cysteine proteinase produced by breast and colorectal carcinomas [2].
• Cathepsin L2 was also expressed by colorectal and breast cancer cell lines as well as by some tumors of diverse origin, including ovarian and renal carcinomas [2].

High impact information on CTSL2

• This finding is in marked contrast with the wide tissue distribution of most cysteine proteinases characterized to date, including cathepsin L, and suggests that cathepsin L2 may play a specialized role in the thymus and testis [2].
• Northern blot analysis of polyadenylated RNAs isolated from a variety of human tissues demonstrated that cathepsin L2 is predominantly expressed in the thymus and testis [2].
• We found that the W135A mutant was rendered inactive against CTSV and CTSL but retained legumain-inhibiting activity [3].
• Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens [4].
• Degradative enzymes examined were cathepsin V/L2 and matrix metalloproteinase (MMP)-1, -2, -7, -9, and -14 [5].

Biological context of CTSL2

• Cystatin M/E is a high affinity inhibitor of cathepsin V and cathepsin L by a reactive site that is distinct from the legumain-binding site. A novel clue for the role of cystatin M/E in epidermal cornification [3].
• In the present study, the entire gene sequence, including 5' and 3' flanking region, and chromosomal localization of human cathepsin L2 were determined [6].
• Cathepsin L2 is a recently described cysteine proteinase with high sequence homology to cathepsin L and other members of the papain superfamily of cysteine proteinases [6].
• The major proteases, cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) are members of a lineage that gave rise to the human cathepsin Ls, Ks and Ss, but while they exhibit similarities in their substrate specificities to these enzymes they differ in having a wider pH range for activity and an enhanced stability at neutral pH [7].

Anatomical context of CTSL2

• Cystatin M/E was also found in the extracellular space in the stratum corneum associated with corneodesmosomes, where it was closely associated with CTSV [8].
• Whereas CTSL and AEP were broadly expressed in epithelial cells of the skin, we found a specific colocalization of cystatin M/E and CTSV in the stratum granulosum and in the root sheets of the hair follicle, using immunofluorescence microscopy [8].
• Cathepsin V, a novel and potent elastolytic activity expressed in activated macrophages [4].
• Cathepsin V protein was detected in human corneal epithelium by western blot analysis, but not in tear fluid [9].
• These findings provide evidence for keratinocyte-specific pivotal functions of cathepsin L-like proteolytic activities in maintenance of epidermis and hair follicles and suggest, that cathepsin V may perform similar functions in human skin [10].

Associations of CTSL2 with chemical compounds

• Cathepsin L2 proteolytic activity on this substrate was abolished by trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, an inhibitor of cysteine proteinases, thus providing additional evidence that the isolated cDNA encodes a functional cysteine proteinase [2].
• We have determined the 1.6 A resolution crystal structure of human cathepsin V associated with an irreversible vinyl sulfone inhibitor [11].
• Sequence analysis of the selected clones identified important antigens including p53, centromere-F, int-2, pentraxin I, integrin beta5, cathepsin L2 and S3 ribosomal protein [12].
• Cathepsin V preferentially released Lys-bradykinin while cathepsin L released bradykinin [13].

Regulatory relationships of CTSL2

• Thus, we generated a transgenic mouse line expressing cathepsin V under the control of the human keratin 14 promoter, which mimics the genuine cathepsin V expression pattern in human skin, by directing it to basal epidermal keratinocytes and the outer root sheath of hair follicles [10].

Other interactions of CTSL2

• Kinetic studies show that Ki values of cystatin M/E for the interaction with CTSV and CTSL are 0.47 and 1.78 nM, respectively [3].
• Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization [14].
• Isolation and characterization of human cathepsin V: a major proteinase in corneal epithelium [9].
• PURPOSE: The mRNA levels of antioxidant enzymes, matrix metalloproteinases, cathepsin V/L2, and tissue inhibitor of matrix metalloproteinases (TIMPs) were determined in keratoconus and normal corneas [5].

Analytical, diagnostic and therapeutic context of CTSL2

• Using immunohistochemistry on normal human skin, we found that cystatin M/E co-localizes with CTSV and CTSL [3].
• Immunoelectron microscopy revealed that cystatin M/E and CTSV are separately transported within the lamellar granules [8].

References