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Gene Review

Lgmn  -  legumain

Mus musculus

Synonyms: AEP, AI746452, AU022324, Asparaginyl endopeptidase, Legumain, ...
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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


Analytical, diagnostic and therapeutic context of Lgmn


  1. Cloning and expression of mouse legumain, a lysosomal endopeptidase. Chen, J.M., Dando, P.M., Stevens, R.A., Fortunato, M., Barrett, A.J. Biochem. J. (1998) [Pubmed]
  2. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Liu, C., Sun, C., Huang, H., Janda, K., Edgington, T. Cancer Res. (2003) [Pubmed]
  3. Origin and molecular specification of striatal interneurons. Marin, O., Anderson, S.A., Rubenstein, J.L. J. Neurosci. (2000) [Pubmed]
  4. Identification of human asparaginyl endopeptidase (legumain) as an inhibitor of osteoclast formation and bone resorption. Choi, S.J., Reddy, S.V., Devlin, R.D., Menaa, C., Chung, H., Boyce, B.F., Roodman, G.D. J. Biol. Chem. (1999) [Pubmed]
  5. Legumain/asparaginyl endopeptidase controls extracellular matrix remodeling through the degradation of fibronectin in mouse renal proximal tubular cells. Morita, Y., Araki, H., Sugimoto, T., Takeuchi, K., Yamane, T., Maeda, T., Yamamoto, Y., Nishi, K., Asano, M., Shirahama-Noda, K., Nishimura, M., Uzu, T., Hara-Nishimura, I., Koya, D., Kashiwagi, A., Ohkubo, I. FEBS Lett. (2007) [Pubmed]
  6. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Manoury, B., Mazzeo, D., Li, D.N., Billson, J., Loak, K., Benaroch, P., Watts, C. Immunity (2003) [Pubmed]
  7. Control of antigen presentation by a single protease cleavage site. Antoniou, A.N., Blackwood, S.L., Mazzeo, D., Watts, C. Immunity (2000) [Pubmed]
  8. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Manoury, B., Mazzeo, D., Fugger, L., Viner, N., Ponsford, M., Streeter, H., Mazza, G., Wraith, D.C., Watts, C. Nat. Immunol. (2002) [Pubmed]
  9. Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice. Zeeuwen, P.L., van Vlijmen-Willems, I.M., Olthuis, D., Johansen, H.T., Hitomi, K., Hara-Nishimura, I., Powers, J.C., James, K.E., op den Camp, H.J., Lemmens, R., Schalkwijk, J. Hum. Mol. Genet. (2004) [Pubmed]
  10. Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms. Wu, W., Luo, Y., Sun, C., Liu, Y., Kuo, P., Varga, J., Xiang, R., Reisfeld, R., Janda, K.D., Edgington, T.S., Liu, C. Cancer Res. (2006) [Pubmed]
  11. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. Chen, J.M., Rawlings, N.D., Stevens, R.A., Barrett, A.J. FEBS Lett. (1998) [Pubmed]
  12. Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice. Shirahama-Noda, K., Yamamoto, A., Sugihara, K., Hashimoto, N., Asano, M., Nishimura, M., Hara-Nishimura, I. J. Biol. Chem. (2003) [Pubmed]
  13. Asparagine endopeptidase is not essential for class II MHC antigen presentation but is required for processing of cathepsin L in mice. Maehr, R., Hang, H.C., Mintern, J.D., Kim, Y.M., Cuvillier, A., Nishimura, M., Yamada, K., Shirahama-Noda, K., Hara-Nishimura, I., Ploegh, H.L. J. Immunol. (2005) [Pubmed]
  14. Autocatalytic activation of human legumain at aspartic acid residues. Halfon, S., Patel, S., Vega, F., Zurawski, S., Zurawski, G. FEBS Lett. (1998) [Pubmed]
  15. Schistosoma mansoni proteases Sm31 (cathepsin B) and Sm32 (legumain) are expressed in the cecum and protonephridia of cercariae. Skelly, P.J., Shoemaker, C.B. J. Parasitol. (2001) [Pubmed]
  16. Multiple cathepsin B isoforms in schistosomula of Trichobilharzia regenti: identification, characterisation and putative role in migration and nutrition. Dvorák, J., Delcroix, M., Rossi, A., Vopálenský, V., Pospísek, M., Sedinová, M., Mikes, L., Sajid, M., Sali, A., McKerrow, J.H., Horák, P., Caffrey, C.R. Int. J. Parasitol. (2005) [Pubmed]
  17. Proteome analysis of secreted proteins during osteoclast differentiation using two different methods: two-dimensional electrophoresis and isotope-coded affinity tags analysis with two-dimensional chromatography. Kubota, K., Wakabayashi, K., Matsuoka, T. Proteomics (2003) [Pubmed]
  18. Colocalization of cystatin M/E and cathepsin V in lamellar granules and corneodesmosomes suggests a functional role in epidermal differentiation. Zeeuwen, P.L., Ishida-Yamamoto, A., van Vlijmen-Willems, I.M., Cheng, T., Bergers, M., Iizuka, H., Schalkwijk, J. J. Invest. Dermatol. (2007) [Pubmed]
  19. DNA vaccination with asparaginyl endopeptidase (Sm32) from the parasite Schistosoma mansoni: anti-fecundity effect induced in mice. Chlichlia, K., Bahgat, M., Ruppel, A., Schirrmacher, V. Vaccine (2001) [Pubmed]
  20. Global gene expression analysis in the bones reveals involvement of several novel genes and pathways in mediating an anabolic response of mechanical loading in mice. Xing, W., Baylink, D., Kesavan, C., Hu, Y., Kapoor, S., Chadwick, R.B., Mohan, S. J. Cell. Biochem. (2005) [Pubmed]
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