Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes

Kobayashi, Hiroshi; Moniwa, Nobuhiko; Sugimura, Motoi; Shinohara, Hiromitsu; Ohi, Hidekazu; Terao, Toshihiko

doi:10.1016/0167-4889(93)90109-3

Cited by 96 publications

(50 citation statements)

References 25 publications

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“…Cathepsin B is capable of degrading specific ECM components (Buck et al, 1992) and activating extracellular proteinases such as soluble and receptor-bound pro-uPA (Kobayashi et al, 1993). Recent studies using molecular genetic techniques to manipulate cathepsin B levels in established tumor cell lines have shown conflicting results for the contributions of cysteine proteinase B to cell motility.…”

Section: Discussionmentioning

confidence: 99%

Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis

et al. 2004

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The cysteine proteinase cathepsin B has been implicated in tumor progression by virtue of its increased mRNA and protein levels, as well as its localization at the invading front of the tumor. In this study, we examined whether blocking cathepsin B expression in human glioblastoma SNB19 cells affects angiogenesis. Stable transfectants of human glioblastoma cells with a plasmid containing antisense cathepsin B cDNA showed decreased migration rates in wound-and spheroid-migration assays. Analysis showed a reduction in VEGF protein and MMP-9 activity in the cathepsin B antisense cDNA-transfected cells. Regarding angiogenesis in vitro, we found that the conditioned medium of glioblastoma cells with downregulated cathepsin B expression reduced cell-cell interaction of human microvascular endothelial cells, resulting in the disruption of capillary-like network formation. Furthermore, a marked reduction in microvasculature development was seen in an in vivo dorsal air sac assay of glioblastoma cells with downregulated cathepsin B expression. Taken together, these results provide evidence that inhibition of cathepsin B expression can suppress glioblastoma-induced neovascularization.

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Section: Discussionmentioning

confidence: 99%

Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis

et al. 2004

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“…Indeed, a substantial amount of evidence points toward their role in the degradation of elastin, collagen, laminin, and other components of the extracellular matrix (29 -33). Furthermore, their role in the coactivation and activation of other proteases, such as the metalloproteases, has also been suggested (34).…”

Section: Discussionmentioning

confidence: 99%

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Burden¹,

Snoddy

Buick

et al. 2008

Molecular Cancer Therapeutics

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Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L -like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L -like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L -like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L -like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis. [Mol Cancer Ther 2008;7(3):538 -47]

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“…However, it also seems possible that MARCKS may regulate in some way the action or secretion of cathepsin B. For example, it is known that cathepsin B can degrade laminin, fibronectin, and collagen (75)(76)(77) and can activate the urokinase-type plasminogen activator associated with tumor invasiveness (78). Studies from our laboratory have shown that the brains of mice completely lacking MARCKS exhibit deficiencies in at least two types of extracellular matrix molecules, laminin and chondroitin sulfate proteoglycans (79).…”

Section: Figmentioning

confidence: 99%

Identification and Characterization of Cathepsin B as the Cellular MARCKS Cleaving Enzyme

Spizz¹,

Blackshear

1997

Journal of Biological Chemistry

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The importance of regulating the cellular concentrations of the myristoylated alanine-rich C kinase substrate (MARCKS), a major cellular substrate of protein kinase C, is indicated by the fact that mice lacking MARCKS exhibit gross abnormalities of central nervous system development and die shortly after birth. We previously identified a novel means of regulating cellular MARCKS concentrations that involved a specific proteolytic cleavage of the protein and implicated a cysteine protease in this process (Spizz, G., and Blackshear, P. J. (1996) J. Biol. Chem. 271, 553-562). Here we show that p40, the carboxyl-terminal fragment resulting from this cleavage of MARCKS, was associated with the mitochondrial/lysosomal pellet fraction of human diploid fibroblasts and that its generation in cells was sensitive to treatment with NH 4 Cl. These data suggest the involvement of lysosomes in the generation and/or stability of p40. The MARCKS-cleaving enzyme (MCE) activity was peripherally associated with a 10,000 ؋ g pellet fraction from bovine liver, and it co-purified with the activity and immunoreactivity of a lysosomal protease, cathepsin B. Cathepsin B catalyzed the generation of p40 from MARCKS in a cell-free system and behaved similarly to the MCE with respect to mutants of MARCKS previously shown to be poor substrates for the MCE. Treatment of fibroblasts with a cell-permeable, specific inhibitor of cathepsin B, CA074-Me, resulted in parallel time-and concentration-dependent inhibition of cathepsin B and MCE activity. Incubation of a synthetic MARCKS phosphorylation site domain peptide with purified cathepsin B resulted in cleavage of the peptide at sites consistent with preferred cathepsin B substrate sites. These data provide evidence for the identity of the MCE as cathepsin B and suggest that this cleavage most likely takes place within lysosomes, perhaps as a result of specific lysosomal targeting sequences within the MARCKS primary sequence. The data also suggest a direct interaction between MARCKS and cathepsin B in cells and leave open the possibility that MARCKS may in some way regulate the protease for which it is a substrate.The myristoylated alanine-rich C kinase substrate (MARCKS) 1 is a prominent cellular substrate for protein kinase C (PKC) (1, 2). Expression of this heat-stable, acidic protein is essential for life, as demonstrated by the perinatal death of mice that are completely deficient in MARCKS (3). Complete lack of expression leads to gross abnormalities of central nervous system development; however, heterozygous mice, which express MARCKS at 50% wild-type levels, appear to be normal.Cellular levels of MARCKS are regulated by both transcriptional and translational mechanisms (4 -14). In addition, we recently demonstrated that the cellular concentrations of MARCKS can also be regulated by a proteolytic event. This proteolytic cleavage results in amino-and carboxyl-terminal fragments of MARCKS that co-exist in cells with the full-length protein. This cleavage of MARCKS was inhibited in intact fi...

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Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes

Cited by 96 publications

References 25 publications

Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis

Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Identification and Characterization of Cathepsin B as the Cellular MARCKS Cleaving Enzyme

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