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Gene Review

M6PR  -  mannose-6-phosphate receptor (cation...

Homo sapiens

Synonyms: 46 kDa mannose 6-phosphate receptor, CD Man-6-P receptor, CD-MPR, Cation-dependent mannose-6-phosphate receptor, MPR 46, ...
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Disease relevance of M6PR


Psychiatry related information on M6PR


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


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].


  1. Differences in the endosomal distributions of the two mannose 6-phosphate receptors. Klumperman, J., Hille, A., Veenendaal, T., Oorschot, V., Stoorvogel, W., von Figura, K., Geuze, H.J. J. Cell Biol. (1993) [Pubmed]
  2. Molecular cloning of mannose-6-phosphate reductase and its developmental expression in celery. Everard, J.D., Cantini, C., Grumet, R., Plummer, J., Loescher, W.H. Plant Physiol. (1997) [Pubmed]
  3. Expression of lysosome-related proteins and genes in the skeletal muscles of inclusion body myositis. Kumamoto, T., Ueyama, H., Tsumura, H., Toyoshima, I., Tsuda, T. Acta Neuropathol. (2004) [Pubmed]
  4. Putative association of polymorphism in the mannose 6-phosphate receptor gene with major depression and Alzheimer's disease. Kölsch, H., Ptok, U., Majores, M., Schmitz, S., Rao, M.L., Maier, W., Heun, R. Psychiatr. Genet. (2004) [Pubmed]
  5. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Nakagawa, T., Setou, M., Seog, D., Ogasawara, K., Dohmae, N., Takio, K., Hirokawa, N. Cell (2000) [Pubmed]
  6. Molecular basis of lysosomal enzyme recognition: three-dimensional structure of the cation-dependent mannose 6-phosphate receptor. Roberts, D.L., Weix, D.J., Dahms, N.M., Kim, J.J. Cell (1998) [Pubmed]
  7. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. Futter, C.E., Pearse, A., Hewlett, L.J., Hopkins, C.R. J. Cell Biol. (1996) [Pubmed]
  8. Neither type of mannose 6-phosphate receptor is sufficient for targeting of lysosomal enzymes along intracellular routes. Kasper, D., Dittmer, F., von Figura, K., Pohlmann, R. J. Cell Biol. (1996) [Pubmed]
  9. Isolation and analysis of the human 46-kDa mannose 6-phosphate receptor gene. Klier, H.J., von Figura, K., Pohlmann, R. Eur. J. Biochem. (1991) [Pubmed]
  10. The overexpressed human 46-kDa mannose 6-phosphate receptor mediates endocytosis and sorting of beta-glucuronidase. Watanabe, H., Grubb, J.H., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  11. Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. Hille-Rehfeld, A. Biochim. Biophys. Acta (1995) [Pubmed]
  12. mVps24p functions in EGF receptor sorting/trafficking from the early endosome. Yan, Q., Hunt, P.R., Frelin, L., Vida, T.A., Pevsner, J., Bean, A.J. Exp. Cell Res. (2005) [Pubmed]
  13. Identification of novel lysosomal matrix proteins by proteome analysis. Kollmann, K., Mutenda, K.E., Balleininger, M., Eckermann, E., von Figura, K., Schmidt, B., Lübke, T. Proteomics (2005) [Pubmed]
  14. The kinetics of mannose 6-phosphate receptor trafficking in the endocytic pathway in HEp-2 cells: the receptor enters and rapidly leaves multivesicular endosomes without accumulating in a prelysosomal compartment. Hirst, J., Futter, C.E., Hopkins, C.R. Mol. Biol. Cell (1998) [Pubmed]
  15. Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy. Dhami, R., Schuchman, E.H. J. Biol. Chem. (2004) [Pubmed]
  16. Invasive properties of murine squamous carcinoma cells: secretion of matrix-degrading cathepsins is attributable to a deficiency in the mannose 6-phosphate/insulin-like growth factor II receptor. Lorenzo, K., Ton, P., Clark, J.L., Coulibaly, S., Mach, L. Cancer Res. (2000) [Pubmed]
  17. Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion. Ioannou, Y.A., Bishop, D.F., Desnick, R.J. J. Cell Biol. (1992) [Pubmed]
  18. Roles of heme insertion and the mannose-6-phosphate receptor in processing of the human myeloid lysosomal enzyme, myeloperoxidase. Nauseef, W.M., McCormick, S., Yi, H. Blood (1992) [Pubmed]
  19. Renin/prorenin receptors. Nguyen, G. Kidney Int. (2006) [Pubmed]
  20. In vitro phosphorylation of the 46-kDa mannose 6-phosphate receptor by casein kinase II. Structural requirements for efficient phosphorylation. Körner, C., Herzog, A., Weber, B., Rosorius, O., Hemer, F., Schmidt, B., Braulke, T. J. Biol. Chem. (1994) [Pubmed]
  21. Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells. Brown, W.J., DeWald, D.B., Emr, S.D., Plutner, H., Balch, W.E. J. Cell Biol. (1995) [Pubmed]
  22. Antigen trafficking and accessory cell function in respiratory epithelial cells. Salik, E., Tyorkin, M., Mohan, S., George, I., Becker, K., Oei, E., Kalb, T., Sperber, K. Am. J. Respir. Cell Mol. Biol. (1999) [Pubmed]
  23. Identification of a low affinity mannose 6-phosphate-binding site in domain 5 of the cation-independent mannose 6-phosphate receptor. Reddy, S.T., Chai, W., Childs, R.A., Page, J.D., Feizi, T., Dahms, N.M. J. Biol. Chem. (2004) [Pubmed]
  24. An ELISA method to quantify the mannose 6-phosphate receptors. Suresh, K., Ramanadham, M., Nadimpalli, S.K. J. Biochem. Biophys. Methods (2002) [Pubmed]
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