Cathepsin D--many functions of one aspartic protease.
For years, it has been held that cathepsin D (CD) is involved in rather non-specific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development, but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans. In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling. Moreover, procathepsin D (pCD), secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy. Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell-pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above-mentioned processes. In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.
Benes
Petr
P
Laboratory of Cell Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, ILBIT A3, Kamenice 3, Brno 625 00, Czech Republic. pbenes@sci.muni.cz
Vetvicka
Vaclav
V
Fusek
Martin
M
D000544:Alzheimer Disease / Q000201:enzymology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011480:Protease Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004792:Enzyme Precursors; D007527:Isoenzymes; D011480:Protease Inhibitors; D002402:Cathepsin D