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Gene Review

M6pr  -  mannose-6-phosphate receptor, cation...

Mus musculus

Synonyms: 46 kDa mannose 6-phosphate receptor, 46mpr, CD Man-6-P receptor, CD-MPR, Cation-dependent mannose-6-phosphate receptor, ...
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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


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


Analytical, diagnostic and therapeutic context of M6pr


  1. mu1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors. Meyer, C., Zizioli, D., Lausmann, S., Eskelinen, E.L., Hamann, J., Saftig, P., von Figura, K., Schu, P. EMBO J. (2000) [Pubmed]
  2. Differential sorting of lysosomal enzymes in mannose 6-phosphate receptor-deficient fibroblasts. Ludwig, T., Munier-Lehmann, H., Bauer, U., Hollinshead, M., Ovitt, C., Lobel, P., Hoflack, B. EMBO J. (1994) [Pubmed]
  3. Targeted disruption of the M(r) 46,000 mannose 6-phosphate receptor gene in mice results in misrouting of lysosomal proteins. Köster, A., Saftig, P., Matzner, U., von Figura, K., Peters, C., Pohlmann, R. EMBO J. (1993) [Pubmed]
  4. Proper sorting of the cation-dependent mannose 6-phosphate receptor in endosomes depends on a pair of aromatic amino acids in its cytoplasmic tail. Schweizer, A., Kornfeld, S., Rohrer, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Expression of the two mannose 6-phosphate receptors is spatially and temporally different during mouse embryogenesis. Matzner, U., von Figura, K., Pohlmann, R. Development (1992) [Pubmed]
  6. Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells. Dressel, R., Raja, S.M., Höning, S., Seidler, T., Froelich, C.J., von Figura, K., Günther, E. J. Biol. Chem. (2004) [Pubmed]
  7. Gene and pseudogene of the mouse cation-dependent mannose 6-phosphate receptor. Genomic organization, expression, and chromosomal localization. Ludwig, T., Rüther, U., Metzger, R., Copeland, N.G., Jenkins, N.A., Lobel, P., Hoflack, B. J. Biol. Chem. (1992) [Pubmed]
  8. Mu 1A deficiency induces a profound increase in MPR300/IGF-II receptor internalization rate. Meyer, C., Eskelinen, E.L., Guruprasad, M.R., von Figura, K., Schu, P. J. Cell. Sci. (2001) [Pubmed]
  9. Characterization of the in vitro retrograde transport of MPR46. Medigeshi, G.R., Schu, P. Traffic (2003) [Pubmed]
  10. Targeted disruption of the cation-dependent or cation-independent mannose 6-phosphate receptor does not decrease the content of acid glycosidases in the acrosome. Chayko, C.A., Orgebin-Crist, M.C. J. Androl. (2000) [Pubmed]
  11. Mutational analysis of the binding site residues of the bovine cation-dependent mannose 6-phosphate receptor. Olson, L.J., Hancock, M.K., Dix, D., Kim, J.J., Dahms, N.M. J. Biol. Chem. (1999) [Pubmed]
  12. Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation. Willenborg, M., Schmidt, C.K., Braun, P., Landgrebe, J., von Figura, K., Saftig, P., Eskelinen, E.L. J. Lipid Res. (2005) [Pubmed]
  13. Insulin-like growth factors and their receptors in muscle development. Szebenyi, G., Rotwein, P. Adv. Exp. Med. Biol. (1991) [Pubmed]
  14. Ligand binding specificities of the two mannose 6-phosphate receptors. Sleat, D.E., Lobel, P. J. Biol. Chem. (1997) [Pubmed]
  15. A casein kinase II phosphorylation site in the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor determines the high affinity interaction of the AP-1 Golgi assembly proteins with membranes. Mauxion, F., Le Borgne, R., Munier-Lehmann, H., Hoflack, B. J. Biol. Chem. (1996) [Pubmed]
  16. Differential regulation of mannose 6-phosphate receptors and their ligands during the myogenic development of C2 cells. Szebenyi, G., Rotwein, P. J. Biol. Chem. (1991) [Pubmed]
  17. Role of LAMP-2 in lysosome biogenesis and autophagy. Eskelinen, E.L., Illert, A.L., Tanaka, Y., Schwarzmann, G., Blanz, J., Von Figura, K., Saftig, P. Mol. Biol. Cell (2002) [Pubmed]
  18. Expression of mannose 6-phosphate receptor messenger ribonucleic acids in mouse spermatogenic and Sertoli cells. O'Brien, D.A., Welch, J.E., Fulcher, K.D., Eddy, E.M. Biol. Reprod. (1994) [Pubmed]
  19. Molecular cloning of the mouse 46-kDa mannose 6-phosphate receptor (MPR 46). Köster, A., Nagel, G., von Figura, K., Pohlmann, R. Biol. Chem. Hoppe-Seyler (1991) [Pubmed]
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