Cathepsin L

Cathepsin L, a lysosomal endopeptidase expressed in most eukaryotic cells, is a member of the papain-like family of cysteine proteinases.1-3 Cathepsin L plays a major role in antigen processing, tumor invasion and metastasis, bone resorption, and turnover of intracellular and secreted proteins involved in growth regulation.4-6 Although commonly recognized as a lysosomal protease, cathepsin L is also secreted. This broad-spectrum protease is potent in degrading several extracellular proteins (laminins, fibronectin, collagens I and IV, elastin, and other structural proteins of basement membranes) as well as serum proteins and cytoplasmic and nuclear proteins.3,7,8

The cathepsin L gene is activated by a variety of growth factors (PDGF and EGF), tumor promoters (including v-ras, v-src and v-mos), and second messengers (cAMP).4,9-12 Expression of cathepsins is regulated by natural inhibitors of cathepsins including the pro-peptides of papain-like cysteine proteases,13 Cystatins, 14,15 and Stefin B.16,17 Squamous cell carcinoma antigen (SSCA)18 and human c-Haras p21 (related to Cystatin b) have been shown to specifically inhibit cathepsin L.19 The conserved cathelin-like pro-piece of defensins (small, cationic antimicrobial peptides), which is only removed during granule release, also inhibits cathepsin L.20

Unlike the precursor forms of other papain family members, the 43 kDa pro-cathepsin L itself is secreted from various cells. Pro-cathepsin L is the major excreted protein of malignantly transformed mouse fibroblasts and is also one of the major acidic cysteine proteases in mammalian cells.2 The conversion from the pro-enzyme to the mature form of cathepsin L is influenced by cell-cell contact and extracellular matrix (ECM) components such as heparin sulfate and glycosaminoglycans.5 The regulation of the cathepsin L gene and the extracellular functions of secreted pro-cathepsin L are tightly coupled.2

Cathepsin L may promote tumor cell invasion and metastasis by catalyzing degradation of the interstitial matrix and basement membranes, thus allowing cancer cells to invade locally and metastasize to distant sites. Several tumor-forming cell lines are known to over-produce cathepsin L.21 The mRNA level of cathepsin L is related to the in vivo metastatic potential of malignantly transformed cells.22 Antisense RNA inhibition of cathepsin L expression reduces tumorigenicity in two malignant cell lines (myeloma SP cells and L cells), suggesting that cathepsin L is a critical factor in tumor growth.23 Cleavage of cathepsin L activates urokinase-type plasminogen activator (uPA) by hydrolysis.24

Proteases participate in tissue degradation and ECM remodeling at the apex of the pre-ovulatory follicle, ultimately leading to follicular rupture on the outer edge of the ovary and release of the mature oocyte.25 Both cathepsin L and ADAMTS1 may play critical roles in the proteolytic events of the ovulation process.26 Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone. High levels of cathepsin L mRNA are also induced by luteinizing hormone in a progesterone receptor-dependent fashion in pre-ovulatory follicles.

Current theories suggest that pulmonary emphysema develops because of progressive loss or derangement of lung elastin through a process mediated by elastinolytic enzymes (including cathepsins B, H, K, L, and S) derived from alveolar macrophages.27-30 Cathepsin L proteolytically inactivates secretory leucoprotease inhibitor (SLPI), alpha1-antitrypsin and two major protease inhibitors of the respiratory tract.31 These observations, combined with the demonstration of increased cathepsin L activity in the epithelial lining fluid of the lungs of emphysema patients, have led to the suggestion that this enzyme may be important in the progression of this disease.


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