Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Affinity-purified lysosomal protease cathepsin D cleaved recombinant human IGFBP-1 to -5 in fragments of defined sizes, while IGFBP-6 was not degraded. To assess the role of cathepsin D for proteolytic processing of IGFBP in vivo, serum from cathepsin D-deficient mice and conditioned media from cathepsin D-deficient fibroblasts and organ explants were analyzed. No differences for the pattern and level of IGFBPs were detected. When conditioned media from fibroblasts were incubated at acid pH, proteolysis of IGFBP-1 and -4 was observed only in media derived from cathepsin D-expressing cells. Additional experiments showed that the proteolysis of IGFBP-4 is mediated by cathepsin D and not by a protease activated by cathepsin D. The IGFBP-4 degrading activities in media from organ explants from cathepsin D-deficient mice were found to be sensitive to inhibitors of aspartyl and cysteine proteases. The data indicate that different classes of acid pH-dependent proteases can contribute to the regulation of IGFBP-4 abundance.
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PMID:Proteolysis of IGFBPs by cathepsin D in vitro and in cathepsin D-deficient mice. 881 69

Various proteinases have been postulated to function in limited proteolysis of insulin-like growth factor binding proteins (IGFBPs) contributing to the regulation of IGF bioavailability. In this study, we report on the in vitro degradation of IGFs and IGFBPs by the purified acidic aspartylprotease cathepsin D that has been shown to proteolyze IGFBP-3. Recombinant human [125I] IGFBP-1 to -5 were processed by cathepsin D to fragments of defined sizes in a concentration dependent manner, whereas IGFBP-6 was not degraded. Ligand blotting revealed that none of the IGFBP-1 or -3 fragments formed by cathepsin D retain their ability to bind IGF. By N-terminal sequence analysis of nonglycosylated IGFBP-3 fragments produced by cathepsin D, at least four different cleavage sites were identified. Some of these cleavage sites were identical or differed by one amino acid from sites used by other IGFBP proteases described. The IGFBP-3 and -4 cleavage sites produced by cathepsin D are located in the nonconserved central region. IGF-I and -II, but not the unrelated platelet-derived growth factor BB, were degraded by cathepsin D in a time and concentration-dependent manner. We speculate that the major functional site of cathepsin D is intracellular and may be involved 1) in the selected clearance either of IGFBP or IGFs via different endocytic pathways or 2) in the general lysosomal inactivation of the IGF system.
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PMID:Proteolysis of insulin-like growth factors (IGF) and IGF binding proteins by cathepsin D. 927 67

The insulin-like growth factor (IGF) system plays an important role in skin. HaCaT human keratinocytes proliferate in response to IGFs and synthesize IGF-binding protein-3 (IGFBP-3). Recently, IGFBP-6 was also identified by NH2-terminal sequencing, but it has not been identified by Western ligand blotting. In the present study, IGFBP-6 was detected in HaCaT-conditioned medium by use of immunoblotting and Western ligand blotting with 125I-labeled IGF-II. Proteolytic activity against IGFBPs, an important mechanism for regulation of their activity, was then studied. An acid-activated, cathepsin D-like protease that cleaved both IGFBP-6 and IGFBP-3 was detected. Although proteolysis did not substantially reduce the size of immunoreactive IGFBP-6, it greatly reduced the ability of IGFBP-6 to bind 125I-IGF-II as determined by Western ligand blotting and solution assay. HaCaT keratinocytes do not express IGF-I mRNA, but IGF-II mRNA and protein expression was detected. These observations suggest the possibility of an autocrine IGF-II loop that is regulated by the relative expression of IGF-II, IGFBP-3, and IGFBP-6, and IGFBP proteases in these keratinocytes, although demonstration of this loop requires further study.
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PMID:HaCaT human keratinocytes express IGF-II, IGFBP-6, and an acid-activated protease with activity against IGFBP-6. 1007 21

The Type-2 insulin-like growth factor receptor (IGF2R) mediates the transport of lysosomal hydrolases to lysosomes and the clearance of insulin-like growth factor II (IGF-II). Mutant mice lacking IGF2R usually die perinatally, but are completely rescued from lethality in the absence of IGF-II. IGF2R/IGF-II-deficient mice have elevated levels of circulating IGF binding protein (IGFBP)-3 and show a strong IGFBP-6 immunoreactivity in all pancreatic islet cells and in secretory granules of different size in acinar cells and interlobular connective tissue of exocrine pancreas. Fibroblasts derived from double mutant mice missort the lysosomal protease cathepsin D, and are able to degrade endocytosed (125I)IGFBP-3 intracellularly, however, with lower efficiency than in control cells. These results show that the deficiency of IGF2R and IGF-II affects the expression and metabolism of IGFBPs in a tissue- and cell type-specific manner.
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PMID:Alteration in pancreatic immunoreactivity of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 and in intracellular degradation of IGFBP-3 in fibroblasts of IGF-II receptor/IGF-II-deficient mice. 1022 7