Disease relevance of M6PR

• In two cell types, the human hepatoma cell line HepG2 and BHK cells double transfected with cDNA's encoding for the human CD-MPR and CI-MPR, we found the two receptors at the same sites: the trans-Golgi reticulum (TGR), endosomes, electron-dense cytoplasmic vesicles, and the plasma membrane [1].
• Recombinant M6PR, purified from Escherichia coli, had specific activity, molecular mass, and kinetic characteristics indistinguishable from those of authentic celery M6PR [2].
• Expressions of mannose 6-phosphate receptor (M6PR), clathrin and hApg5 and hApg12 were analyzed in muscle biopsy specimens from patients with s-IBM, amyotrophic lateral sclerosis (ALS) or peripheral neuropathy and in normal human muscle specimens by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) [3].

Psychiatry related information on M6PR

• No significant association of the CD-MPR C-allele with Alzheimer's disease was observed [4].

High impact information on M6PR

• Thus, KIF13A transports M6PR-containing vesicles and targets the M6PR from TGN to the plasma membrane via direct interaction with the AP-1 adaptor complex [5].
• We now report the three-dimensional structure of a glycosylation-deficient, yet fully functional form of the extracytoplasmic domain of the bovine CD-MPR (residues 3-154) complexed with mannose 6-phosphate at 1.8 A resolution [6].
• We show that the HRP-loaded lysosomes are lysosomal-associated membrane protein-1 (LAMP-1) positive, mannose-6-phosphate receptor (M6PR) negative. and contain active acid hydrolase [7].
• Human MPR 46 and MPR 300 were expressed in these cells to test whether overexpression of a single type of MPR can restore transport of lysosomal proteins to lysosomes [8].
• Mouse embryonic fibroblasts that are deficient in the two mannose 6-phosphate receptors (MPRs) MPR 46 and MPR 300 missort the majority (> or = 85%) of soluble lysosomal proteins into the medium [8].

Biological context of M6PR

• No correlation between the genomic organization and known protein domains of the MPR46 was apparent [9].
• The human MPR46 gene is distributed over 12 kb and is divided into seven exons (110-1573 bp) [9].
• From a genomic library in EMBL 3, two overlapping clones for the human 46-kDa mannose 6-phosphate receptor (MPR46) were isolated, which span the entire coding sequence [9].
• The overexpressed human 46-kDa mannose 6-phosphate receptor mediates endocytosis and sorting of beta-glucuronidase [10].
• Additional functions have been reported, e.g., export of newly synthesized lysosomal enzymes from the cell by MPR 46 or a--probably indirect--participation in growth factor-mediated signal transduction by MPR 300 [11].

Anatomical context of M6PR

• Adventitious expression of hrs or a mVps4p mutant deficient in ATPase activity caused a redistribution of both mVps24p and the M6PR to the resultant clustered/enlarged early endosomes [12].
• Mouse embryonic fibroblasts defective in both MPR (MPR 46-/- and MPR 300-/-) are known to secrete the lysosomal matrix proteins [13].
• These data suggest that the two MPRs exit the TGR via the same coated vesicles, but that upon arrival in the endosomes CD-MPR is more rapidly than CI-MPR, segregated into ATV which probably are destined to recycle MPRs to TGR [1].
• At steady state, most M6PR are distributed within the trans-Golgi and trans-Golgi network and in vacuolar structures distributed in the peripheral cytoplasm [14].
• We therefore hypothesized that lipid accumulation in ASMKO macrophages led to abnormalities in M6PR trafficking and/or degradation, resulting in reduced enzyme uptake [15].

Associations of M6PR with chemical compounds

• SCC-VII cells express the 46 kDa cation-dependent M6P receptor (MPR46), but intracellular retention of procathepsins B, D, and L is not affected by ammonium chloride and chloroquine, agents known to perturb the M6P receptor system [16].
• Moreover, the sequence of about 150 amino acids within the luminal domain of MPR46, which is homologous to the 15 repeats that constitute the luminal domain of the 300-kDa mannose 6-phosphate receptor (MPR300), does not correlate with intron/exon borders [9].
• The recombinant intracellular and secreted enzyme forms were normally processed and phosphorylated; the secreted enzyme had mannose-6-phosphate moieties and bound the immobilized 215-kD mannose-6-phosphate receptor (M6PR) [17].
• Studies using receptor-specific ligands to inhibit enzyme uptake revealed that in normal cells rhASM was taken up by a combination of mannose and mannose 6-phosphate receptors (MR and M6PR, respectively), whereas in the ASMKO cells the M6PR had a minimal role in rhASM uptake [15].
• These data confirmed a close relationship between the development of photosynthetic capacity, mannitol synthesis, and M6PR activity [2].

Physical interactions of M6PR

• Thus, if the M6PR is important in the intracellular transport of MPO, it is the phosphorylated mature MPO that is directed to the lysosomal compartment by this system.(ABSTRACT TRUNCATED AT 400 WORDS)[18]
• The M6P-R is a clearance receptor that binds exclusively the glycosylated forms of renin and prorenin [19].

Enzymatic interactions of M6PR

• Tryptic phosphopeptide mapping showed that casein kinase II phosphorylates MPR 46 in vitro at the same site that is phosphorylated in vivo [20].

Regulatory relationships of M6PR

• These results are most consistent with the interpretation that PI 3-kinase regulates the trafficking of lysosomal enzymes by interfering with a M6PR-dependent sorting event in the TGN [21].

Other interactions of M6PR

• Functional blockade of KIF13A reduced cell surface expression of the M6PR [5].
• MPR46 and MPR300 have therefore diverged from a common ancestral gene before introduction of the present intron sequences [9].
• (3) What role does the mannose-6-phosphate receptor (M6PR) system play in the delivery of MPO to the lysosome [18]?
• Double immunolabeling for the CD-MPR and the asialoglycoprotein receptor, which mainly recycles between endosomes and the plasma membrane, revealed that these two receptors were concentrated in different subpopulations of endosomal ATV [1].
• The FITC-labeled Ags colocalized with an early endosomal marker (anti-cathepsin D), a late endosomal marker (M6PR), a lysosomal marker (CD63), and with 3-(2, 4-dinitroanilino)-3'-aminomethyldipropylamine, a marker of acidic vesicles [22].

Analytical, diagnostic and therapeutic context of M6PR

• Expression of M6PR mRNA was normal in the ASMKO cells, although Western blotting revealed more receptors in these cells when compared with normal [15].
• Sequence analyses showed M6PR to be a member of the aldo-keto reductase superfamily, which includes both animal and plant enzymes [2].
• A structure-based sequence alignment was performed that predicts that domain 5 contains the four conserved key residues (Gln, Arg, Glu, and Tyr) identified as essential for carbohydrate recognition by the CD-MPR and domains 3 and 9 of the CI-MPR, but lacks two cysteine residues predicted to form a disulfide bond within the binding pocket [23].
• Using this affinity-purified antibody and the antiserum to goat MPR 46, as well as an affinity-purified MSC1 antibody that is specific for MPR 46, we developed an ELISA method to quantify both the receptors [24].
• In the present study, MPR 300 and MPR 46 were purified from goat liver by phosphomannan affinity chromatography, and polyclonal antibodies were raised in rabbits [24].

References