Secretion and processing mechanisms of procathepsin L in bone resorption

Kakegawa, Hisao; Tagami, Kahori; Ohba, Yasuo; Sumitani, Koji; Kawata, Tomio; Katunumaa, Nobuhiko

doi:10.1016/0014-5793(95)00790-g

Cited by 23 publications

(27 citation statements)

References 19 publications

(19 reference statements)

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“…However, it has been reported that secreted cathepsin L plays a major role in the process of bone resorption by osteoclasts (Kakegawa et al, 1993(Kakegawa et al, , 1995. In this experiment, we clearly demonstrated that the level of secreted procathepsin L was correlated with the capability of bone invasion of the cancer cells.…”

Section: Discussionsupporting

confidence: 64%

“…Procathepsin L secreted from BHY cells may be in a free form, because BHY cells secreted only a trace level of TIMP1. Procathepsin L was reported to be activated in acidic conditions (Kakegawa et al, 1995). Therefore, procathepsin L secreted from BHY cells may be easily activated at the front of bone invasion, and the activated cathepsin L might degrade the demineralized bone matrix (mainly composed of type-I collagen).…”

Section: Discussionmentioning

confidence: 99%

“…The result of Western blotting for MMP2 was identical to that of zymog raphy. Cathepsin L was recently reported to play a major role in the process of bone resorption by osteoclasts (Kakegawa et al, 1993(Kakegawa et al, , 1995. Therefore we examined the expression of cathepsin L in the cancer cells.…”

Section: Production Of Matrix-degrading Enzymes and Their Inhibitors mentioning

confidence: 99%

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Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines

et al. 1997

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Oral squamous-cell carcinoma represents 1 to 2% of all human malignancies; its incidence in Japan is more than 5,500 cases per year. They are characterized by a high degree of local invasiveness (bone and muscular invasion) and a high rate of metastasis to cervical lymph nodes, but a low rate of metastases to distant organs. Tumor cells secrete matrix-degrading enzymes, or induce host cells to elaborate degrading enzymes, or activate pro-enzymes which are secreted by host cells (Fidler, 1990;Liotta and Stetler-Stevenson, 1991;Aznavoorian et al., 1993;Sato et al., 1994). We have reported that augmented net activity of matrix metalloproteinases (MMPs) (especially MMP2) in bladder-cancer cells markedly enhanced their extravasation at the distant organ site, and slightly enhanced metastasis to lymph nodes, but marginally affected primary tumor growth, and local invasion (Kawamata et al., 1995a,b). On the other hand, the activity of matrix-degrading enzymes is in part influenced by intrinsic inhibitors [tissue inhibitors of matrix metalloproteinase (TIMPs) and plasminogen activator inhibitors (PAIs)], which are produced either by the host or by tumor cells (Liotta and Stetler-Stevenson, 1991;Aznavoorian et al., 1993). Proteolysis of extracellular matrix is not a unique property of tumor cells. Matrix-degrading enzymes are secreted by a variety of normal cells, and matrix proteolysis and cell migration are known physiologic steps. The apparent difference between normal and pathologic processes is in the regulation of their activity (Stetler-Stevenson, 1996).The environment of the organ affects production, secretion and activation of extracellular-matrix-degrading enzymes of tumor cells or host cells, and that these factors modify the invasion and the metastatic behavior of several carcinoma cells in nude mice (Fidler, 1990;Nakajima et al., 1990;Kameyama et al., 1993). Therefore, tumorigenicity, invasiveness and metastatic potential of tumor cells should be evaluated by inoculation of the cells at the organ site orthotopic to the tumor.We have established human oral squamous-cancer cell lines, BHY and HN, originally derived from non-metastatic cancer and metastatic cancer respectively. Furthermore, we have developed a new in vivo model for studying tumorigenicity, invasion and metastasis of oral cancer cells inoculated with human gingival fibroblasts into the masseter muscle of nude mice. In this study, in order to determine the factors associated with muscular and bone invasion or lymph-node and distant metastases of oral squamouscancer cells, we analyzed the expression and/or activity of a variety of matrix-degrading enzymes and their inhibitors in the newly established cells, and assessed the invasive or metastatic potentials of the cells by orthotopic site inoculation in nude mice. MATERIAL AND METHODS Cells and cell cultureBHY and HN cells were isolated from non-metastatic and metastatic oral squamous cancer respectively. Cancer tissues were minced into 1-mm 3 pieces and placed in 100-mm Petri dishes (Falcon; Bec...

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Production Of Matrix-degrading Enzymes and Their Inhibitors mentioning

confidence: 99%

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Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines

et al. 1997

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“…It is translated as preprocathepsin L, which is then processed to procathepsin L with a molecular mass of 39 kDa and further processed to the mature cathepsin L, which exists in either singlechain (30 kDa) or two-chain (25 and 5 kDa) forms (9, 20 -22). Cathepsin L is suggested to participate in turnover of intracellular or endocytosed proteins (8), degradation of ECM proteins, antigen processing and presentation (23), bone resorption (24,25), and various other processes. Many growth factors and oncogenes can stimulate cathepsin L expression (26 -29), and increased expression of cathepsin L is commonly associated with malignant transformation (30,31).…”

Section: Discussionmentioning

confidence: 99%

Cysteine Cathepsins Are Central Contributors of Invasion by Cultured Adenosylmethionine Decarboxylase-Transformed Rodent Fibroblasts

et al. 2004

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Adenosylmethionine decarboxylase (AdoMetDC), a key enzyme in the biosynthesis of polyamines, is often up-regulated in cancers. We have demonstrated previously that overexpression of AdoMetDC alone is sufficient to transform NIH 3T3 cells and induce highly invasive tumors in nude mice. Here, we studied the transformation-specific alterations in gene expression induced by AdoMetDC by using cDNA microarray and two-dimensional electrophoresis technologies. We specifically tried to identify the secreted proteins contributing to the high invasive activity of the AdoMetDC-transformed cells. We found a significant increase in the expression and secretion of procathepsin L, which was cleaved and activated in the presence of glycosaminoglycans (heparin), and a smaller increase in cathepsin B. Inhibition of the cathepsin L and B activity by specific peptide inhibitors abrogated the invasive capacity of the AdoMetDC transformants in Matrigel. The transformed cells also showed a small increase in the activity of gelatin-degrading matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator activities, neither of which was sensitive to the inhibitors of cathepsin L and B. Furthermore, the invasive potency of the transformed cells remained unaffected by specific inhibitors of MMPs. The results suggest that cysteine cathepsins are the main proteases contributing to the high invasiveness of the AdoMetDC-transformed cells and that the invasion potential is largely independent of activation of the MMPs.

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“…It has been implicated in a range of processes including turnover of proteins involved in growth regulation, tumor invasion and metastasis (21), and bone resorption (22). The mouse analogue of procathepsin is secreted from transformed mouse fibroblasts and has been at first called major excreted protein (11).…”

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confidence: 99%

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

Jerala

Žerovnik

Kidrič

et al. 1998

Journal of Biological Chemistry

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Synthesis of proteases as inactive zymogens is a very important mechanism for the regulation of their activity. For lysosomal proteases proteolytic cleavage of the propeptide is triggered by the acidic pH. By using fluorescence, circular dichroism, and NMR spectroscopy, we show that upon decreasing the pH from 6.5 to 3 the propeptide of cathepsin L loses most of the tertiary structure, but almost none of the secondary structure is lost. Another partially structured intermediate, prone to aggregation, was identified between pH 6.5 and 4. The conformation, populated below pH 4, where the activation of cathepsin L occurs, is not completely unfolded and has the properties of molten globule, including characteristic binding of the 1-anilinonaphthalene-8-sulfonic acid. This pH unfolding of the propeptide parallels a decrease of its affinity for cathepsin L and suggests the mechanism for the acidic zymogen activation. Addition of anionic polysaccharides that activate cathepsin L already at pH 5.5 unfolds the tertiary structure of the propeptide at this pH. Propeptide of human cathepsin L which is able to fold independently represents an evolutionary intermediate in the emergence of novel inhibitors originating from the enzyme proregions.All lysosomal and most other proteases are synthesized in the form of inactive precursors (1, 2). Propeptides are generally located N-terminal to the mature enzyme, and activation of the enzyme is accomplished by cis-or trans-cleavage of the propeptide. Propeptides vary from a few (e.g. trypsin) to more than 200 residues (e.g. cathepsin C). Longer propeptides are generally strong and specific inhibitors of their mature enzymes (3-7). In most cases propeptides are also indispensable for correct folding of the enzymes (8). In some enzymes folding of the mature form is extremely slow, and the propeptide assists in overcoming the kinetic barrier (9), which may also be overcome by physicochemical factors such as high ionic strength in subtilisin, for example (10). Proenzymes are quite often more stable than mature enzymes (11, 12) and can represent a pool of latent enzyme until the activation occurs in the proper conditions. Propeptides are also involved in targeting to specific organelles (13, 14); they can affect posttranslational modification such as glycosylation (15) and mediate interactions with other molecules (16,17). Propeptides can be cleaved either by other proteases or by intra-or intermolecular autocatalysis. pH change is one of the most common environmental parameters responsible for triggering the activation of proteases, occurring in cysteine, aspartic acid, and metalloproteases (1,18,19). Low pH is thought either to increase the susceptibility of the propeptide as a substrate due to the protonation of groups close to the cleavage site or to cause a conformational change in the propeptide or enzyme.Cathepsin L is one of the most active cysteine proteases and accounts for most of the lysosomal cysteine protease activity (20). It has been implicated in a range of processes incl...

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Secretion and processing mechanisms of procathepsin L in bone resorption

Cited by 23 publications

References 19 publications

Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines

Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines

Cysteine Cathepsins Are Central Contributors of Invasion by Cultured Adenosylmethionine Decarboxylase-Transformed Rodent Fibroblasts

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

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