Disease relevance of Lgmn

• Recombinant mouse legumain was expressed in human embryonic kidney 293 cells by use of a vector containing a cytomegalovirus promoter [1].
• Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy [2].
• Using focal injections of retrovirus into the ventral telencephalon in vitro, we demonstrate that most striatal interneurons tangentially migrate from the medial ganglionic eminence (MGE) or the adjacent preoptic/anterior entopeduncular areas (POa/AEP) and express the NKX2.1 homeodomain protein [3].
• Implantation in nude mice of 293 cells transfected with the legumain cDNA and constitutively expressing high levels of the protein significantly reduced hypercalcemia induced by PTHrP by about 50%, and significantly inhibited the increase in OCL surface and in OCL number expressed per mm(2) bone area and per mm bone surface induced by PTHrP [4].
• Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced [5].

High impact information on Lgmn

• Here we show that this step can be performed in B lymphocytes by asparagine endopeptidase (AEP), which targets different asparagine residues in the lumenal domain of human and mouse invariant chain [6].
• The mutant antigen is highly resistant to proteolysis by AEP and crude lysosomal extracts and is dramatically impaired in its ability to be processed and presented to T cells [7].
• Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells [8].
• Absence of cystatin M/E causes unrestricted activity of its target protease legumain in hair follicles and epidermis, which is the exact location where cystatin M/E is normally expressed [9].
• A novel legumain-activated, cell-impermeable doxorubicin prodrug LEG-3 was designed to be activated exclusively in the tumor microenvironment [10].

Biological context of Lgmn

• Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases [11].
• Here, we showed that legumain, the only asparaginyl endopeptidase of the mammalian genome, is highly expressed by neoplastic, stromal, and endothelial cells in solid tumors [10].
• Expression of legumain, a novel asparaginyl endopeptidase, in tumors was identified from gene expression profiling and tumor tissue array analysis [2].
• Cells overexpressing legumain possessed increased migratory and invasive activity in vitro and adopted an invasive and metastatic phenotype in vivo, inferring significance of legumain in tumor invasion and metastasis [2].

Anatomical context of Lgmn

• Thus, the AEP deficiency caused the accumulation of macromolecules in the lysosomes, highlighting a pivotal role of AEP in the endosomal/lysosomal degradation system [12].
• In the wild-type kidney where the expression of AEP was exceedingly high among various organs, the localization of AEP was mainly found in the lamp-2-positive late endosomes in the apical region of the proximal tubule cells [12].
• In the absence of AEP, presentation to primary T cells of OVA and myelin oligodendrocyte glycoprotein, two Ags that contain asparagine residues within or in proximity to the relevant epitopes was unimpaired [13].
• Human legumain was characterized following overexpression in a murine cell line as the C-terminal Ig-fusion protein [14].
• Hemoglobin, released from the ingested red blood cells, is degraded by a variety of parasite proteases, including Sm31 (cathepsin B) and Sm32 (schistosome legumain) [15].

Associations of Lgmn with chemical compounds

• Asparaginyl endopeptidase (AEP)/legumain, an asparagine-specific cysteine proteinase in animals, is an ortholog of plant vacuolar processing enzyme (VPE), which processes the exposed asparagine residues of various vacuolar proteins [12].
• Cathepsin (Cat) L, a lysosomal cysteine protease essential for the development to CD4 and NK T cells, fails to be processed into its mature two-chain form in AEP-deficient cells [13].
• Autocatalytic activation of human legumain at aspartic acid residues [14].
• Substitution of alanine for the putative catalytic cysteine, or for either of two strictly conserved histidine residues, partly or wholly eliminated autoactivation but not the ability of wild-type legumain to correctly process the variants to the properly sized proteins [14].
• We show by site-directed mutagenesis that the catalytic residues of mammalian legumain, a recently discovered lysosomal asparaginycysteine endopeptidase, form a catalytic dyad in the motif His-Gly-spacer-Ala-Cys [11].

Regulatory relationships of Lgmn

• Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis [5].

Other interactions of Lgmn

• In these cells of AEP-deficient mice, the lamp-2-positive membrane structures were found to be greatly enlarged [12].
• We conclude that AEP is essential for processing of Cat L but not for class II MHC-restricted Ag presentation [13].
• Schistosoma mansoni proteases Sm31 (cathepsin B) and Sm32 (legumain) are expressed in the cecum and protonephridia of cercariae [15].
• TrCB1.1 zymogen was unable to catalyse its own activation, but was trans-processed and activated by S. mansoni asparaginyl endopeptidase (SmAE aka. S. mansoni legumain) [16].
• Cathepsins, osteopontin, legumain, macrophage inflammatory protein-1alpha, and other proteins were observed as up- or down-regulated proteins and are discussed in the context of osteoclast differentiation and bone resorption [17].

Analytical, diagnostic and therapeutic context of Lgmn

• Whereas CTSL and AEP were broadly expressed in epithelial cells of the skin, we found a specific colocalization of cystatin M/E and CTSV in the stratum granulosum and in the root sheets of the hair follicle, using immunofluorescence microscopy [18].
• DNA vaccination with asparaginyl endopeptidase (Sm32) from the parasite Schistosoma mansoni: anti-fecundity effect induced in mice [19].
• The validity of the microarray data was established with the increased expression of bone-related genes such as pleiotrophin, osteoglycin, and legumain upon four-point bending and confirmation of increased expression of selected genes by real-time PCR [20].

References