High impact information on M6pr

• MPR46 fails to recycle back from the endosome to the TGN, indicating that AP-1 is required for retrograde endosome to TGN transport of the receptor [1].
• Fibroblasts that lack the CI-MPR, like those lacking the CD-MPR, exhibit a milder phenotype and are only partially impaired in sorting [2].
• To investigate the in vivo function of the MPR46, we generated MPR46-deficient mice using gene targeting in embryonic stem cells [3].
• The addition of the Phe18-Trp19 motif of the CD-MPR to the cytoplasmic tail of the lysosomal membrane protein Lamp1 was sufficient to partially impair its delivery to lysosomes [4].
• The 67-amino acid cytoplasmic tail of the cation-dependent mannose 6-phosphate receptor (CD-MPR) contains a signal(s) that prevents the receptor from entering lysosomes where it would be degraded [4].

Biological context of M6pr

• The phenotype of MPR46 -/- mice was normal, indicating mechanisms that compensate the MPR46 deficiency in vivo [3].
• We have analyzed the distribution of MPR46 and MPR300 transcripts during mouse embryogenesis by in situ hybridization [5].
• Using lymphoblasts and mouse embryonal fibroblast lines from Mpr300 and Mpr46 knockout mice, we show here that both receptors are not essential for CTL-induced apoptosis [6].
• We have cloned the mouse CD-MPR gene and also a very unusual processed-type CD-MPR pseudogene [7].
• These two features of the pseudogene suggest that expression of the CD-MPR gene may be regulated by use of different promoters and/or alternative splicing [7].

Anatomical context of M6pr

• Mammalian cells express two mannose 6-phosphate receptors, MPR46 and MPR300, both of which mediate the targeting of lysosomal enzymes to lysosomes [5].
• High expression of MPR46 was observed at sites of hemopoiesis and in the thymus while MPR300 was highly expressed in the cardiovascular system [5].
• In mu1A-adaptin-deficient fibroblasts, the homologous MPR46 accumulates in endosomes due to a block in retrograde transport to the trans-Golgi network [8].
• We characterized the retrograde transport of MPR46 from endosomes to the TGN by an in vitro transport assay using mouse fibroblast cell lines [9].
• Mouse testicular germ cells are known to express both the cation-independent (CI-MPR) and cation-dependent (CD-MPR) forms of the mannose 6-phosphate receptors, but the CD-MPR is predominant [10].

Associations of M6pr with chemical compounds

• Exon 1 encodes the 5'-untranslated region of the mRNA, the others (exons 2-7) encode the luminal, transmembrane, and cytoplasmic domains of the CD-MPR [7].
• In addition, mutation of the single histidine residue, His-105, within the binding site diminished the binding of the receptor to ligand, but did not eliminate the ability of the CD-MPR to release ligand under acidic conditions [11].
• This leads to massive accumulation of unesterified cholesterol in the endo/lysosomal compartment of the MPR46/300-deficient fibroblasts, a phenotype similar to that of the NPC patient fibroblasts [12].
• In contrast to the 13-fold rise in IGF-II/CIMPR mRNA levels, transcript levels for the CDMPR remained constant during C2 cell development, enzymatic activities of two lysosomal enzymes did not change, and only a small increment was detected at a single time point in the expression of several lysosomal enzyme mRNAs [13].

Physical interactions of M6pr

• Ligands precipitated by the CD-MPR appeared identical to those bound by the CI-MPR, with apparent affinity constants ranging between 7 and 28 nM [14].

Regulatory relationships of M6pr

• Thus, the affinity of AP-1 for membranes and in vivo transport of cathepsin D were measured for MPR-negative cells re-expressing various CD-MPR mutants [15].

Other interactions of M6pr

• The cation-dependent mannose 6-phosphate receptor (CDMPR) lacks an IGF-II-binding site and participates only in the intracellular trafficking of lysosomal enzymes [16].
• The mannose 6-phosphate receptor MPR46 mediates sorting of lysosomal enzymes and recycles between the trans-Golgi network and endosomes [9].
• The steady-state level of 300-kDa mannose 6-phosphate receptor was slightly lower in LAMP-2-deficient hepatocytes, whereas that of 46-kDa mannose 6-phosphate receptor was decreased to 30% of controls due to a shorter half-life [17].
• When poly(A) tracts were selectively removed from germ cell RNAs by ribonuclease H treatment, identical 1.3-kb CD-MPR mRNAs were detected in pachytene spermatocytes and round spermatids, indicating that the size difference between the 1.4- and 1.6-kb transcripts is due to variations in poly(A) tail length.(ABSTRACT TRUNCATED AT 250 WORDS)[18]

Analytical, diagnostic and therapeutic context of M6pr

• However, Northern blot analysis demonstrates that the CD-MPR is variably expressed in adult mouse tissues and during mouse development [7].
• Molecular cloning of the mouse 46-kDa mannose 6-phosphate receptor (MPR 46) [19].
• To elucidate the key amino acids involved in conveying this carbohydrate specificity, site-directed mutagenesis studies were conducted on the extracytoplasmic domain of the bovine CD-MPR [11].

References