Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mild cathepsin D digest of fibronectin only contained single-chain peptides of 200, 140 and 70 kDa and double-chain fragments of about 300 and 140 kDa containing the C-terminal disulfide link. Among the single-chain fragments the 200 kDa peptide was a precursor of the 140 kDa and 70 kDa peptides. The latter was correlated to the N-terminal and the former to the central region of the fibronectin subunit chains.
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PMID:A large cathepsin D-derived fragment from the central part of the fibronectin subunit chains. 685 43

Circular dichroism spectra, thermal transition profiles and proteolytic susceptibility showed that different regions in the multidomain protein fibronectin exhibit different sensitivity against urea denaturation. A 70-kDa fragment obtained by cathepsin D treatment which comprises the N-terminal part of the fibronectin chains, exhibited in 8M urea a spectrum, at 20 degrees C, identical to that of the native fragment and its thermal unfolding was shifted to lower temperatures by only 10 degrees C. The central portions of the fibronectin chains were remarkably unfolded under the same conditions as clearly demonstrated by the spectra and transition profiles of a cathepsin D-raised 125/140-kDa fragment which originates from this region. When fibronectin or its fragments were exposed to 4 or 8M urea at 4 degrees C and the urea subsequently dialysed off, the spectra and transition curves recorded were very similar to those of the native proteins. Nevertheless, this treatment introduced local conformational changes which resulted in the creation of three new cleavage sites for chymotrypsin. The most prominent one was found to be located in the central part of the middle region and no sites were created in the N-terminal 70-kDa region. In the conjunction with sequence information [Petersen et al. (1983) Proc. Natl. Acad. Sci. USA 80, 137-141] it may be concluded that the disulfide rich domains, made up by regions of internal homology of types I and II in the N-terminal portion of fibronectin, exhibit a remarkable conformational stability, whereas the disulfide free middle region which contains type III domains, is much less stable. Some domains in this region are particularly sensitive to urea denaturation and are irreversibly affected already by 4M urea at 4 degrees C. Therefore, the use of high urea concentrations for the elution of fibronectin from affinity columns may lead to an at least partially irreversible unfolding of some domains and a loss of functions associated with these structural elements.
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PMID:Discrimination of different domains in fibronectin on the basis of their stability against urea denaturation. 687 82

Fibronectin consists of two very similar subunits connected by disulfide bonds close to their C-terminal ends. After short digestion with cathepsin D a fragment containing an intact subunit linked to a C-terminal piece of the other chain was isolated. Both possible combinations were realized. The remnant chain, removed by reduction, had a relative molecular mass (Mr) of 65000 or 75000, respectively, whether it originated from the shorter or the longer fibronectin subunit. After prolonged cathepsin D digestion another disulfide-linked fragment of Mr 90000 containing peptide chains of Mr 65000 and Mr 36000 was found. The same fragment also formed during prolonged digestion of a previously described cathepsin D-derived heparin-binding piece of Mr 140000 which consisted of disulfide-linked chains of Mr 65000 and Mr 75000. The cut-off material emerged as a mixture of two similar heparin binding peptides of Mr 35000 and Mr 37000. The residual disulfide-linked peptide of Mr 90000 was retained by heparin-Sepharose, too, indicating that the non-degraded chain of Mr 65000 also contained a heparin-binding site. Plasminolysis of the Mr 140000 fragment first liberated the two individual chains and subsequently cleaved the longer one into two domains of nearly equal size. A rather basic one (pI 8.4-8.8) with low cystine content bound to heparin-Sepharose, while the other cystine-rich and more acidic domain (pI 5.0-5.8) was not retained. The shorter peptide chain, also showing affinity to heparin, was attacked by plasmin rather slowly. It, however, also appeared to be composed of two differently charged regions as it had an isoelectric point in the neutral range (pI 6.4-6.8) in spite of its heparin-binding properties. In the longer chain the heparin-binding domain was located in a distal position to the C-terminal disulfide link. The same is assumed for the shorter chain by reason of homology.
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PMID:Early and late cathepsin D-derived fragments of fibronectin containing the C-terminal interchain disulfide cross-link. 707 31

Resolution of a cathepsin D digest of plasma fibronectin on heparin-Sepharose yielded, in addition to non-bound and weakly retained material (Fraction I and II), various fragments which were not eluted until 0.25M NaCl (Fraction III) and 0.5M NaCl (Fraction IV) was applied. Fraction III contained predominantly a peptide of Mr 70 000 originating from the N-terminus of the fibronectin subunits as well as high molecular weight precursors yielding the Mr 70 000 peptide by further digestion. All those peptides were retained by immobilized denatured collagen, type I, indicating the presence of the known gelatin-binding domain. In addition, they contained a transamidase-sensitive site as revealed from a digest of fibronectin previously labelled with [14C]putrescine by a transamidase-mediated reaction. Plasminolysis of the fragment of Mr 70 000 resulted in two peptides of Mr 30 000 and 40 000, only the former being retained by heparin-Sepharose. Fraction IV contained a fragment of Mr 140 000 which, after reduction, dissociated into two peptides of Mr 75 000 and 65 000. Apparently, it included the disulfide bond(s) connecting the two fibronectin subunits close to their C-terminal ends. Partial digestion of the two electrophoretically separated peptide chains with protease of Staphylococcus aureus V8 yielded for each chain a number of peptides with equal electrophoretic migration rate. In addition, however, some peptides were different in the two digests. The results were consistent with an identical or homologous structure of the two peptide chains with an additional sequence in the longer chain. The latter (Mr 75 000) uniquely contained a transamidase susceptible site as demonstrated by processing of [14C]putrescine-labelled fibronectin.
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PMID:Location of heparin-binding sites of fibronectin. Detection of a hitherto unrecognized transamidase sensitive site. 723 39

The alternatively spliced type III connecting segment (IIICS) of fibronectin (Fn) contains an amino acid sequence, CS-1, which is recognized by the integrin receptor, alpha 4 beta 1. Plasma Fn inhibits alpha 4 beta 1-dependent binding of lymphocytes and monocytes to CS-1 containing Fn derivatives poorly, suggesting limited exposure of the CS-1 sequence in Fn. To test the availability of CS-1 in plasma Fn, an antibody was raised to the synthetic peptide CS-1. The CS-1 sequence was found to be minimally exposed in plasma Fn; and immobilization of Fn, a model of matrix deposition, caused only a modest increase in its exposure. Digestion of Fn with selected proteases, however, induced substantial expression of the CS-1 sequence. The acid protease cathepsin D generated fragments of 31-33.5 kDa from the COOH-terminal heparin-binding domain of Fn which possessed high immunoreactivity with anti-CS-1. Digestion of Fn with cathepsin B also resulted in the exposure of CS-1 sequence in a 140 kDa fragment. Although the digestion of Fn with neutral proteases (neutrophil elastase, cathepsin G, chymotrypsin, trypsin) generated fragments from the COOH-terminal heparin-binding domain of similar molecular weight as with cathepsin D, the exposure of CS-1 did not occur. Exposure of the CS-1 region by the cathepsins was supported by cell adhesion experiments; digestion of Fn with cathepsins D and B transformed inert plasma Fn to an effective inhibitor of adhesion of lymphoblastoid B and T cells (Ramos, Jurkat, Molt-4) to an immobilized CS-1 conjugate. These results suggest that exposure of the CS-1 sequence in plasma Fn by proteolysis with cathepsins D and B, enzymes implicated in several pathological processes, may serve a regulatory function in cell adhesion. The adhesive function of the CS-1 region in intact Fn appears to be suppressed by the native conformation of the molecule.
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PMID:Proteolysis regulates exposure of the IIICS-1 adhesive sequence in plasma fibronectin. 871 84

Cell surface molecules on adherent cells that bind 125I-labeled fibronectin or its 70-kDa N-terminal fragment were identified by cross-linking with factor XIIIa and by photoaffinity labeling. Such cross-linking caused the 70-kDa fragment to become associated irreversibly to cell layers and was greater in cells treated with lysophosphatidic acid, an enhancer of fibronectin assembly and strong modulator of cell shape. Cross-linking of the 70-kDa fragment with factor XIIIa was to molecules that migrated in discontinuous sodium dodecyl sulfate-polyacrylamide gels at the top of the 3.3% stacking gel and near the top of the separating gel. Estimated sizes of these large apparent molecular mass molecules (LAMMs) were >>3 MDa and approximately 3 MDa. The label in 70-kDa fragment conjugated with 125I-sulfosuccinimidyl 2-(p-azidosalicylamido)-1, 3'-dithiopropionate was associated with >>3-MDa LAMMs without reduction and with approximately 3-MDa LAMMs after reduction and transfer of the cleavable label. The LAMMs were expressed on monolayer cells shortly after adherence, required both 1% Triton X-100 and 2 M urea for efficient extraction, and were susceptible to digestion with trypsin but not to cathepsin D digestion. Complexes of 125I-70-kDa fragment and LAMMs were also susceptible to limited acid digestion and Glu-C protease digestion but were not cleaved by chondroitin lyase or heparitinase. Neither the uncleaved complexes nor the cleavage products were immunoprecipitated with anti-fibronectin antibodies directed toward epitopes outside the 70-kDa region. Thus, cell surface molecules that are either very large or not dissociated in sodium dodecyl sulfate comprise the labile matrix assembly sites for fibronectin.
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PMID:Cross-linking of the NH2-terminal region of fibronectin to molecules of large apparent molecular mass. Characterization of fibronectin assembly sites induced by the treatment of fibroblasts with lysophosphatidic acid. 896 87

In 87 breast cancer patients, the immunohistochemical expression of the basement membrane (BM)-degrading enzyme cathepsin D (CD) was correlated with the expression of extracellular matrix components, with growth fraction, steroid receptor content and with the other conventional prognostic variables in breast cancer. Only 6.25% of tumours had laminin-defined BM, while 86.8% showed staining for fibronectin. CD was also identified in carcinoma cells (cancer cell CD; CCCD) and in stromal cells (stromal cell CD; SCCD). Forty-five percent of tumours showed CCCD and 47.5%, SCCD expression. CCCD expression was significantly correlated with positive oestrogen receptor content, with low Ki-67 and high PCNA score and with SCCD expression. There was no correlation with collagen type IV, laminin or fibronectin. SCCD expression was positively correlated with collagen type IV, laminin expression and tumour grade. The data suggest that the CD of tumour cells and the CD of tumour-associated macrophages have different roles in breast cancer. CCCD correlates with cell proliferation and is regulated by oestrogens, while SCCD relates to cell differentiation, is oestrogen-independent, and has a proteolytic role in the breakdown of BM components.
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PMID:Immunohistochemical expression of cathepsin D in correlation with extracellular matrix component, steroid receptor status and proliferative indices in breast cancer. 946 71

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
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PMID:Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. 967 87

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.
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PMID:[Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?]. 984 Oct 98

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10-50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.
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PMID:Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1007 Dec 34


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