Disease relevance of Mep1a

• Thus, disruption of the meprin beta allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin alpha in kidney and intestine [1].
• Meprin-alpha in chronic diabetic nephropathy: interaction with the renin-angiotensin axis [2].
• In the primary rat tumors and transplanted rat or nude mouse tumors, MEP-1 reacted specifically with the fibroblastlike cells but not with the histiocytelike cells or xanthoma cells [3].
• Immunological properties of a model polyepitope immunogen (MEP-1) consisting of selected determinants from envelope proteins of hepatitis B virus (HBV) were examined [4].
• The binding of a mouse monoclonal antibody (MEP-1) reacting specifically with type I pneumocytes was assessed on paraffin sections of normal specimens as well as those with pulmonary fibrosis induced by bleomycin or radiation treatment [5].

High impact information on Mep1a

• The Mep-1 gene is closely linked to a gene that controls isoenzyme patterns of phosphoglycerate kinase (Pgk-2) [6].
• The gene controlling the activity of meprin (Mep-1) maps on chromosome 17 to the right of the D end of the major histocompatibility complex [6].
• Mep-1 gene controlling a kidney metalloendopeptidase is linked to the major histocompatibility complex in mice [6].
• Homooligomers of meprin alpha are secreted; oligomers containing meprin beta are plasma membrane associated [1].
• In the present study, we found that endogenous MBP ligands are highly expressed in the brush border epithelial cells of kidney-proximal tubules by immunohistochemistry, and both meprin alpha and beta (meprins), as novel endogenous MBP ligands, have been identified through affinity chromatography and mass spectrometry [7].

Biological context of Mep1a

• The Mep-1 gene on chromosome 17 in mice controls the activity of meprin, a kidney brush border metalloendopeptidase [8].
• To further study the relationship between the major histocompatibility complex and Mep-1, a linkage study was conducted [8].
• The Mep-1 locus provides a new genetic marker for the future mapping of this important area of the mouse genome [8].
• Site-directed mutagenesis of active site residues demonstrated that replacement of a hydrophobic residue by a basic amino acid enabled the meprin alpha protease to cleave gastrin [9].
• Homology models of the mouse meprin alpha and beta protease domains, based on the astacin crystal structure, revealed active site differences that can account for the marked differences in substrate specificity of the two subunits [10].

Anatomical context of Mep1a

• The meprin alpha subunit, a multidomain metalloproteinase, is synthesized as a type I membrane protein and proteolytically cleaved during biosynthesis in the endoplasmic reticulum (ER), consequently losing its membrane attachment and COOH-terminal domains [11].
• The 3.6-kilobase mRNA meprin alpha subunit message was also detected in the small intestine of the rat but not in mice [12].
• The present work shows that reducing agents solubilized meprin alpha subunits (approximately 90%), but not beta subunits, from mouse kidney brush border membranes [13].
• These studies show that meprin alpha and beta are expressed in leukocytes of the mouse mesenteric lymph node, and meprin alpha, but not beta, decreased during intestinal inflammation [14].
• The work herein, however, reports that low levels of meprin alpha subunit mRNA and protein are detectable in mouse intestine and are present in increasing concentrations from the duodenum to the ileum [15].

Associations of Mep1a with chemical compounds

• Western blotting with antisera specific to the meprin-alpha and the meprin-beta subunits established that the only form of meprin present in urine samples was derived from meprin-alpha [16].
• In addition, another proposed zinc binding ligand, H167, in the conserved (HEXXH) zinc binding motif of the meprin alpha protease domain was replaced by an alanine residue [17].
• However, all changes in meprin alpha subunit NH2-terminal structure were found to decrease the thermal stability of the enzyme [18].
• The alpha(1-528) mutant was as active as wild-type meprin alpha against a bradykinin substrate, but had no activity against azocasein, and it, as all other mutants, was more vulnerable to extensive degradation by proteases than the wild-type protein [19].
• These results indicate that there is no one specific glycosylation site or type of oligosaccharide (high mannose- or complex-type) that determines apical sorting, but that core N-linked carbohydrates are required for optimal enzymatic activity and for secretion of meprin alpha [20].

Physical interactions of Mep1a

• Both wild-type meprin alpha and the DeltaMAM mutant interact with the molecular chaperones calnexin and calreticulin in the endoplasmic reticulum [21].

Other interactions of Mep1a

• Proximity of the Mep-1 gene to H-2D on chromosome 17 in mice [8].
• A testis-specific gene Tpx-1 maps between Pgk-2 and Mep-1 on mouse chromosome 17 [22].
• In this study, we have used the mouse meprin alpha subunit as a model to test this hypothesis of zymogen activation of the astacins [18].
• Purification of mouse MEP-1, a nuclear protein which binds to the metal regulatory elements of genes encoding metallothionein [23].

Analytical, diagnostic and therapeutic context of Mep1a

• Assignment of Mep 1a to mouse chromosome band 17C1-D1 by in situ hybridization [24].
• Double stainings with both MEP-1 and RM-1 or TRPM-3 did not detect any double positive cells [3].
• Immunoelectron microscopy using these MAbs showed that the fibroblastlike cells were the major cell component of the primary and transplanted rat tumors and that their cell membrane was stained positively with MEP-1, but not for RM-1 or TRPM-3 [3].
• Results obtained by DNA cytofluorometry with 4,6-diamidino-2-phenylindole dihydrochloride staining or by the combined method of DNA cytofluorometry and indirect immunofluorescence, using MEP-1, RM-1, and TRPM-3, indicate that MEP-1-positive cells are neoplastic cells of rat MFH having proliferation activity [3].
• Electrophoretic mobility-shift assays showed that MTF-1, produced in COS cells, produces a slower-migrating band compared with that obtained with purified MEP-1 [25].

References