Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mannose 6-phosphate receptors: new twists in the tale

Key Points

  • ;Mannose 6-phosphate (M6P) receptors (the CD-MPR and CI-MPR) are type-I integral membrane glycoproteins that constitute the family of p-type lectins. They bind to M6P-containing lysosomal acid hydrolases and transport them from the Golgi to the endosomal–lysosomal system.

  • X-ray crystallographic studies have provided an understanding of the molecular mechanisms that govern carbohydrate recognition by the MPRs, and IGF-II recognition by the CI-MPR. A relatively deep carbohydrate-recognition domain accounts for the numerous interactions between the CD-MPR and its carbohydrate ligands. The liganded versus unliganded molecule shows a considerable conformational change that enables ligand binding by the receptor.

  • The MPRs have a complex intracellular trafficking itinerary that includes cycling between the Golgi and the endosomes, and delivering acid hydrolases to the endosomal compartments. The anterograde trafficking of the MPRs is through GGA-assisted packaging into AP1-containing clathrin-coated carriers, whereas the retrieval from the endosomal system occurs through a combination of the PACS-1/AP1 and TIP47/Rab9 pathways. MPRs that reach the cell surface are internalized rapidly by AP2.

  • The CI-MPR has further functions at the cell surface that include internalization of IGF-II for degradation in lysosomes and activation of latent transforming growth factor (TGF)-β1.

  • Loss of heterozygosity at the CI-MPR locus has been reported in several human cancers. In several instances, the M6P- and IGF-II-binding domains of the remaining allele have been found to have mutations. Where examined, most of the mutations disrupted M6P- and/or IGF-II-binding properties. This supports the proposal that loss of normal CI-MPR function contributes to carcinogenesis, making it a candidate tumour-suppressor gene.


The two mannose 6-phosphate (M6P) receptors were identified because of their ability to bind M6P-containing soluble acid hydrolases in the Golgi and transport them to the endosomal–lysosomal system. During the past decade, we have started to understand the structural features of these receptors that allow them to do this job, and how the receptors themselves are sorted as they pass through various membrane-bound compartments. But trafficking of acid hydrolases is only part of the story. Evidence is emerging that one of the receptors can regulate cell growth and motility, and that it functions as a tumour suppressor.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The MPRs are type-I transmembrane glycoproteins.
Figure 2: The crystal structure of the extracytoplasmic region of the bovine CD-MPR.
Figure 3: Comparison of the CI-MPR domain 11 and CD-MPR structures.
Figure 4: A schematic representation of the subcellular localization and trafficking itinerary of the MPRs.
Figure 5: Sorting signals on MPR tails.
Figure 6: The structure of the GGA3 VHS domain bound to its ligand.
Figure 7: Architecture of the trans-Golgi network and its relevance to MPR trafficking.

Accession codes


Protein Data Bank


  1. 1

    Dahms, N. M. & Hancock, M. K. P-type lectins. Biochim. Biophys. Acta. 1572, 317–340 (2002).

    CAS  Google Scholar 

  2. 2

    Kornfeld, S. Structure and function of the mannose 6-phosphate/insulin like growth factor II receptors. Annu. Rev. Biochem. 61, 307–330 (1992).

    CAS  Google Scholar 

  3. 3

    Hille-Rehfeld, A. Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. Biochim. Biophys. Acta. 1241, 177–194 (1995).

    Google Scholar 

  4. 4

    Le Borgne, R. & Hoflack, B. Protein transport from the secretory to the endocytic pathway in mammalian cells. Biochim. Biophys. Acta. 1404, 195–209 (1998).

    CAS  Google Scholar 

  5. 5

    Lobel, P., Dahms, N. M. & Kornfeld, S. Cloning and sequence analysis of the cation-independent mannose 6-phosphate receptor. J. Biol. Chem. 263, 2563–2570 (1988).

    CAS  Google Scholar 

  6. 6

    Hancock, M. K., Haskins, D. J., Sun, G. & Dahms, N. M. Identification of residues essential for carbohydrate recognition by the insulin-like growth factor II/mannose 6-phosphate receptor. J. Biol. Chem. 277, 11255–11264 (2002).

    CAS  Google Scholar 

  7. 7

    Marron-Terada, P. G., Hancock, D. J., Haskins, D. J. & Dahms, N. M. Recognition of Dictyostelium discoideum lysosomal enzymes is conferred by the amino-terminal carbohydrate binding site of the insulin-like growth factor II/mannose 6-phosphate receptor. Biochemistry 39, 2243–2253 (2000).

    CAS  Google Scholar 

  8. 8

    Schmidt, B., Kiecke-Siemsen, C., Waheed, A., Braulke, T. & von Figura, K. Localization of the insulin-like growth factor II binding site to amino acids 1508–1566 in repeat 11 of the mannose 6-phosphate/insulin-like growth factor II receptor. J. Biol. Chem. 270, 14975–14982 (1995).

    CAS  Google Scholar 

  9. 9

    Garmroudi, F., Devi, G., Slentz, D. H., Schaffer, B. S. & MacDonald, R. G. Truncated forms of the insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor encompassing the IGF-II binding site: characterization of a point mutation that abolishes IGF-II binding. Mol. Endocrinol. 10, 642–651 (1996). References 6–9 characterize the carbohydrate-binding domain and the IGF-II-binding site on the CI-MPR.

    CAS  Google Scholar 

  10. 10

    Meresse, S., Ludwig, T., Frank, R. & Hoflack, B. Phosphorylation of the cytoplasmic domain of the bovine cation-independent mannose 6-phosphate receptor. Serines 2421 and 2492 are the targets of a casein kinase II associated to the Golgi-derived HAI adaptor complex. J. Biol. Chem. 265, 18833–18842 (1990).

    CAS  Google Scholar 

  11. 11

    Rosorius, O. et al. Characterization of phosphorylation sites in the cytoplasmic domain of the 300 kDa mannose 6-phosphate receptor. Biochem. J. 292, 833–838 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  12. 12

    Schweizer, A., Kornfeld, S. & Rohrer, J. Cysteine 34 of the cytoplasmic tail of the cation-dependent mannose 6-phosphate receptor is reversibly palmitoylated and required for normal trafficking and lysosomal enzyme sorting. J. Cell Biol. 132, 577–584 (1996).

    CAS  Google Scholar 

  13. 13

    York, S. J., Arneson, L. S., Gregory, W. T., Dahms, N. M. & Kornfeld, S. The rate of internalization of the mannose 6-phosphate/insulin-like growth factor II receptor is enhanced by multivalent ligand binding. J. Biol. Chem. 274, 1164–1171 (1999).

    CAS  Google Scholar 

  14. 14

    Byrd, J. C. & MacDonald, R. G. Mechanisms for high affinity mannose 6-phosphate ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor. Negative cooperativity and receptor oligomerization. J. Biol. Chem. 275, 18638–18646 (2000).

    CAS  Google Scholar 

  15. 15

    Byrd, J. C., Park, J. H., Schaffer, B. S., Garmroudi, F. & MacDonald, R. G. Dimerization of the insulin-like growth factor II/mannose 6-phosphate receptor. J. Biol. Chem. 275, 18647–18656 (2000).

    CAS  Google Scholar 

  16. 16

    Roberts, D. L., Weix, D. J., Dahms, N. M. & Kim, J. -J. P. Molecular basis of lysosomal enzyme recognition: three-dimensional structure of the cation-dependent mannose 6-phosphate receptor. Cell 93, 639–648 (1998).

    CAS  Google Scholar 

  17. 17

    Olson, L. J., Zhang, J., Lee, Y. C., Dahms, N. M. & Kim, J. -J. P. Structural basis for recognition of phosphorylated high mannose oligosaccharides by the cation-dependent mannose 6-phosphate receptor. J. Biol. Chem. 274, 29889–29896 (1999).

    CAS  Google Scholar 

  18. 18

    Olson, L. J., Zhang, J., Dahms, N. M. & Kim, J. -J. P. Twists and turns of the CD-MPR: ligand-bound versus ligand-free receptor. J. Biol. Chem. 277, 10156–10161 (2002). References 16–18 provide useful insights into the structural basis for M6P-containing ligand recognition by the CD-MPR.

    CAS  Google Scholar 

  19. 19

    Brown, J. et al. Structure of a functional IGF2R fragment determined from the anomalous scattering of sulfur. EMBO J. 21, 1054–1062 (2002). This work presents a high-resolution crystal structure of the eleventh domain of the CI-MPR that functions as the IGF-II-binding domain.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. 20

    Zeslawski, W. et al. The interaction of insulin-like growth factor-I with the N-terminal domain of IGFBP-5. EMBO J. 20, 3638–3644 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. 21

    Devi, G. R., Byrd, J. C., Slentz, D. H. & MacDonald, R. G. An insulin-like growth factor II (IGF-II) affinity-enhancing domain localized within extracytoplasmic repeat 13 of the IGF-II/mannose 6-phosphate receptor. Mol. Endocrinol. 12, 1661–1672 (1998).

    CAS  Google Scholar 

  22. 22

    Linnell, J., Groeger, G. & Hassan, A. B. Real time kinetics of insulin-like growth factor II (IGF-II) interaction with the IGF-II/mannose 6-phosphate receptor: the effects of domain 13 and pH. J. Biol. Chem. 276, 23986–23991 (2001).

    CAS  Google Scholar 

  23. 23

    Rohrer, J. & Kornfeld, R. Lysosomal hydrolase mannose 6-phosphate uncovering enzyme resides in the trans-Golgi network. Mol. Biol. Cell 12, 1623–1631 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. 24

    Klumperman, J. et al. Differences in the endosomal distributions of the two mannose 6-phosphate receptors. J. Cell Biol. 121, 997–1010 (1993). This report established that the two receptors exit the trans -Golgi network through AP1-positive clathrin-coated buds and vesicles.

    CAS  Google Scholar 

  25. 25

    Campbell, C. H. & Rome, L. H. Coated vesicles from rat liver and calf brain contain lysosomal enzymes bound to mannose 6-phosphate receptors. J. Biol. Chem. 258, 13347–13352 (1983).

    CAS  Google Scholar 

  26. 26

    Schulze-Lohoff, E., Hasilik, A. & von Figura, K. Cathepsin D precursors in clathrin-coated organelles from human fibroblasts. J. Cell Biol. 101, 824–829 (1985). References 25 and 26 showed that clathrin-coated vesicles function as transport carriers for lysosomal enzymes en route from the Golgi to the endosomal–lysosomal compartments.

    CAS  Google Scholar 

  27. 27

    Johnson, K. F. & Kornfeld, S. The cytoplasmic tail of the mannose 6-phosphate/insulin-like growth factor-II receptor has two signals for lysosomal enzyme sorting in the Golgi. J. Cell Biol. 119, 249–257 (1992).

    CAS  Google Scholar 

  28. 28

    Johnson, K. F. & Kornfeld, S. A His–Leu–Leu sequence near the carboxyl terminus of the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor is necessary for the lysosomal enzyme sorting function. J. Biol. Chem. 267, 17110–17115 (1992).

    CAS  Google Scholar 

  29. 29

    Chen, H. J., Remmler, J., Delaney, J. C., Messner, D. J. & Lobel, P. Mutational analysis of the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor. A consensus casein kinase II site followed by 2 leucines near the carboxyl terminus is important for intracellular targeting of lysosomal enzymes. J. Biol. Chem. 268, 22338–22346 (1993).

    CAS  Google Scholar 

  30. 30

    Chen, H. J., Yuan, J. & Lobel, P. Systematic mutational analysis of the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor cytoplasmic domain. An acidic cluster containing a key aspartate is important for function in lysosomal enzyme sorting. J. Biol. Chem. 272, 7003–7012 (1997). References 27–30 establish the role of the AC-LL signal in trafficking of the mannose 6-phosphate receptors from the trans -Golgi network to endosomes.

    CAS  PubMed  Google Scholar 

  31. 31

    Mauxion, F., Le Borgne, R., Munier-Lehmann, H. & Hoflack, B. 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. J. Biol. Chem. 271, 2171–2178 (1996).

    CAS  Google Scholar 

  32. 32

    Honing S., Sosa M., Hille-Rehfeld, A. & von Figura, K. The 46-kDa mannose 6-phosphate receptor contains multiple binding sites for clathrin adaptors. J. Biol. Chem. 272, 19884–19890 (1997).

    CAS  Google Scholar 

  33. 33

    Poussu A., Lohi, O. & Lehto, V. P. Vear, a novel Golgi-associated protein with VHS and γ-adaptin 'ear' domains. J. Biol. Chem. 275, 7176–7183 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Hirst, J. et al. A family of proteins with γ-adaptin and VHS domains that facilitate trafficking between the trans-Golgi network and the vacuole/lysosome. J. Cell Biol. 149, 67–80 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  35. 35

    Dell'Angelica, E. C. et al. GGAs: A family of ADP ribosylation factor-binding proteins related to adaptors and associated with the Golgi complex. J. Cell Biol. 149, 81–94 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 36

    Boman, A. L., Zhang, C., Zhu, X. & Kahn, R. A. A family of ADP-ribosylation factor effectors that can alter membrane transport through the trans-Golgi. Mol. Biol. Cell 11, 1241–1255 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37

    Takatsu, H., Yoshino, K. & Nakayama, K. Adaptor γ ear homology domain conserved in γ-adaptin and GGA proteins that interact with γ-synergin. Biochem. Biophys. Res. Commun. 271, 719–725 (2000). References 33–37 cite the five groups that simultaneously and independently discovered the GGA family of adaptors.

    CAS  PubMed  Google Scholar 

  38. 38

    Puertollano, R., Aguilar, R. C., Gorshkova, I., Crouch, R. J. & Bonifacino, J. S. Sorting of mannose 6-phosphate receptors mediated by the GGAs. Science 292, 1712–1716 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Zhu, Y., Doray, B., Poussu, A., Lehto, V. P. & Kornfeld, S. Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Science 292, 1716–1718 (2001).

    CAS  PubMed  Google Scholar 

  40. 40

    Takatsu, H., Katoh, Y., Shiba, Y. & Nakayama, K. Golgi-localizing, γ-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains. J. Biol. Chem. 276, 28541–28545 (2001). References 38–40 implicated the GGAs in sorting of mannose 6-phosphate receptors at the trans -Golgi network.

    CAS  PubMed  Google Scholar 

  41. 41

    Misra, S., Puertollano, R., Kato, Y., Bonifacino, J. S. & Hurley, J. H. Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains. Nature 415, 933–937 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42

    Shiba, T. et al. Structural basis for recognition of acidic-cluster dileucine sequence by GGA1. Nature 415, 937–941 (2002). References 41 and 42 demonstrate the structural basis for the recognition of the AC–LL signal in the cytoplasmic tail of the MPR by the VHS domain of the GGA protein.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43

    Jacobsen, L. et al. The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett. 511, 155–158 (2002).

    CAS  Google Scholar 

  44. 44

    Doray, B., Bruns, K., Ghosh, P. & Kornfeld, S. Interaction of the cation-dependent mannose 6-phosphate receptor with GGA proteins. J. Biol. Chem. 277, 18477–18482 (2002).

    CAS  Google Scholar 

  45. 45

    Puertollano, R., Randazzo, P. A., Presley, J. F., Hartnell, L. M. & Bonifacino, J. S. The GGAs promote ARF-dependent recruitment of clathrin to the TGN. Cell. 105, 93–102 (2001).

    CAS  Google Scholar 

  46. 46

    Dittie, A. S., Thomas, L., Thomas, G. & Tooze, S. A. Interaction of furin in immature secretory granules from neuroendocrine cells with the AP-1 adaptor complex is modulated by casein kinase II phosphorylation. EMBO J. 16, 4859–4870 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47

    Le Borgne, R., Schmidt, A., Mauxion, F., Griffiths, G. & Hoflack B. Binding of AP-1 Golgi adaptors to membranes requires phosphorylated cytoplasmic domains of the mannose 6-phosphate/insulin-like growth factor II receptor. J. Biol. Chem. 268, 22552–22556 (1993).

    CAS  Google Scholar 

  48. 48

    Ohno, H. et al. The medium subunits of adaptor complexes recognize distinct but overlapping sets of tyrosine-based sorting signals. J. Biol. Chem. 273, 25915–25921 (1998).

    CAS  Google Scholar 

  49. 49

    Owen, D. J. & Evans, P. R. A structural explanation for the recognition of tyrosine-based endocytic signals. Science. 282, 1327–1332 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50

    Bremnes, T., Lauvrak, V., Lindqvist, B. & Bakke, O. A region from the medium chain adaptor subunit (μ) recognizes leucine- and tyrosine-based sorting signals. J. Biol. Chem. 273, 8638–8645 (1998).

    CAS  Google Scholar 

  51. 51

    Rapoport, I., Chen, Y. C., Cupers, P., Shoelson, S. E. & Kirchhausen, T. Dileucine-based sorting signals bind to the β chain of AP-1 at a site distinct and regulated differently from the tyrosine-based motif-binding site. EMBO J. 17, 2148–2155 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  52. 52

    Black, M. W. & Pelham, H. R. A selective transport route from Golgi to late endosomes that requires the yeast GGA proteins. J. Cell Biol. 151, 587–600 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. 53

    Costaguta, G., Stefan, C. J., Bensen, E. S., Emr S. D. & Payne, G. S. Yeast GGA coat proteins function with clathrin in Golgi to endosome transport. Mol. Biol. Cell 12. 1885–1896 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. 54

    Hirst, J., Lindsay, M. R. & Robinson, M. S. GGAs: Roles of the different domains and comparison with AP-1 and clathrin. Mol. Biol. Cell 12, 3573–3588 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. 55

    Ladinsky, M. S., Mastronarde, D. N., McIntosh, J. R., Howell, K. E. & Staehelin, L. A. Golgi structure in three dimensions: functional insights from the normal rat kidney cell. J. Cell Biol. 144, 1135–1149 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 56

    Marsh, B. J., Mastronarde, D. N., Buttle, K. F., Howell, K. E. & McIntosh, J. R. Organellar relationships in the Golgi region of the pancreatic β-cell line, HIT-T15, visualized by high resolution electron tomography. Proc. Natl Acad. Sci. USA 98, 2399–2406 (2001).

    CAS  Google Scholar 

  57. 57

    Doray, B., Ghosh, P., Griffith, J., Geuze, H. & Kornfeld, S. Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science, 297, 1700–1703 (2002). This work showed that GGAs and AP1 colocalize within clathrin-coated buds and vesicles at the trans -Golgi network (TGN) of mammalian cells, which indicates a cooperative model for AP1 and GGAs in trafficking of MPRs from the TGN to endosomes, as opposed to the independent pathways proposed in yeast.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58

    Doray, B., Bruns, K., Ghosh, P. & Kornfeld, S. A. Autoinhibition of the ligand-binding site of GGA1/3 VHS domains by an internal acidic cluster-dileucine motif. Proc. Natl Acad. Sci. USA 99, 8072–8077 (2002).

    CAS  Google Scholar 

  59. 59

    Huang, F., Nesterov, A., Carter, R. E. & Sorkin, A. Trafficking of yellow-fluorescent-protein-tagged μ1 subunit of clathrin adaptor AP-1 complex in living cells. Traffic 2, 345–357 (2001). The first evidence of AP1 in anterograde trafficking of MPRs using live-cell imaging techniques.

    CAS  Google Scholar 

  60. 60

    Waguri, S. et al. Visualization of TGN to endosomes trafficking through fluorescently labeled MPR and AP-1 in living cells. Mol. Biol. Cell 14, 142–155 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  61. 61

    Le Borgne, R. & Hoflack, B. Mannose 6-phosphate receptors regulate the formation of clathrin-coated vesicles in the TGN. J. Cell Biol. 137, 335–345 (1997).

    CAS  Google Scholar 

  62. 62

    Umeda, A., Meyerholz, A. & Ungewickell, E. Identification of the universal cofactor (auxilin 2) in clathrin coat dissociation. Eur. J. Cell Biol. 79, 336–342 (2000).

    CAS  Google Scholar 

  63. 63

    Greener, T., Zhao, X., Nojima, H., Eisenberg, E. & Greene, L. E. Role of cyclin G-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells. J. Biol. Chem. 275, 1365–1370 (2000).

    CAS  PubMed  Google Scholar 

  64. 64

    Hannan, L. A., Newmyer, S. L. & Schmid, S. L. ATP- and cytosol-dependent release of adaptor proteins from clathrin-coated vesicles: a dual role for Hsc70. Mol. Biol. Cell 9, 2217–2229 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65

    Nakagawa, T. et al. A novel motor, KIF13A, transports mannose 6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103, 569–581 (2000).

    CAS  Google Scholar 

  66. 66

    Ludwig, T., Griffiths, G. & Hoflack, B. Distribution of newly synthesized lysosomal enzymes in the endocytic pathway of normal rat kidney cells. J. Cell Biol. 115, 1561–1572 (1991).

    CAS  Google Scholar 

  67. 67

    Press, B., Feng, Y., Hoflack, B. & Wandingerness, A. Mutant rab7 causes the accumulation of cathepsin D and cation-independent mannose 6-phosphate receptor in an early endocytic compartment. J. Cell Biol. 140, 1075–1089 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. 68

    Bucci, C., Thomsen, P., Nicoziani, P., McCarthy, J. & van Deurs, B. Rab7: a key to lysosome biogenesis. Mol. Biol. Cell 11, 467–480 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  69. 69

    Shiba, Y., Takatsu, H., Shin, H. W. & Nakayama, K. γ-adaptin interacts directly with rabaptin-5 through its ear domain. J. Biochem. 131, 327–336 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70

    Stenmark, H., Vitale, G., Ullrich, O. & Zerial, M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell 83, 423–432 (1995).

    CAS  PubMed  Google Scholar 

  71. 71

    Bock, J. B., Klumperman, J., Davanger, S. & Scheller, R. H. Syntaxin 6 functions in trans-Golgi network vesicle trafficking. Mol. Biol. Cell 8, 1261–1271 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. 72

    Prekeris, R., Klumperman, J., Chen, Y. A. & Scheller, R. H. Syntaxin 13 mediates cycling of plasma membrane proteins via tubulovesicular recycling endosomes. J. Cell Biol. 143, 957–971 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73

    Steegmaier, M., Klumperman, J., Foletti, D. L., Yoo, J. S. & Scheller, R. H. Vesicle-associated membrane protein 4 is implicated in trans-Golgi network vesicle trafficking. Mol. Biol. Cell 10, 1957–1972 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. 74

    Klumperman, J., Kuliawat, R., Griffith, J. M., Geuze, H. J. & Arvan, P. Mannose 6-phosphate receptors are sorted from immature secretory granules via adaptor protein AP-1, clathrin, and syntaxin 6-positive vesicles. J. Cell Biol. 141, 359–371 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. 75

    Peden, A. A., Park, G. Y. & Scheller, R. H. The di-leucine motif of vesicle-associated membrane protein 4 is required for its localization and AP-1 binding. J. Biol. Chem. 276, 49183–49187 (2001).

    CAS  Google Scholar 

  76. 76

    Simonsen, A., Gaullier, J. M., D'Arrigo, A. & Stenmark, H. The Rab5 effector EEA1 interacts directly with syntaxin-6. J. Biol. Chem. 274, 28857–28860 (1999).

    CAS  Google Scholar 

  77. 77

    Storrie, B. & Desjardins, M. The biogenesis of lysosomes: is it a kiss and run, continuous fusion and fission process? Bioessays 18, 895–903 (1996).

    CAS  Google Scholar 

  78. 78

    Schweizer, A., Kornfeld, S. & Rohrer, J. Proper sorting of the cation-dependent mannose 6-phosphate receptor in endosomes depends on a pair of aromatic amino acids in its cytoplasmic tail. Proc. Natl Acad. Sci. USA 94, 14471–14476 (1997). This work established the importance of a di-aromatic sequence on the cytoplasmic tail of the CD-MPR in preventing it from entering lysosomes.

    CAS  Google Scholar 

  79. 79

    Diaz, E. & Pfeffer, S. R. TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking. Cell 93, 433–443 (1998).

    CAS  Google Scholar 

  80. 80

    Orsel, J. G., Sincock, P. M., Krise, J. P. & Pfeffer, S. R. Recognition of the 300-kDa mannose 6-phosphate receptor cytoplasmic domain by 47-kDa tail-interacting protein. Proc. Natl Acad. Sci. USA 97, 9047–9051 (2000).

    CAS  Google Scholar 

  81. 81

    Carroll, K. S. et al. Role of Rab9 GTPase in facilitating receptor recruitment by TIP47. Science 292, 1373–1376 (2001).

    CAS  Google Scholar 

  82. 82

    Barbero, P., Bittova, L. & Pfeffer, S. R. Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J. Cell Biol. 156, 511–518 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83

    Riederer, M. A., Soldati, T., Shapiro, A. D., Lin, J. & Pfeffer, S. R. Lysosome biogenesis requires Rab9 function and receptor recycling from endosomes to the trans-Golgi network. J. Cell Biol. 125, 573–582 (1994). References 79–83 provide evidence that TIP47/Rab9 mediates sorting of the MPRs at the late endosome and has a role in retrograde trafficking to the Golgi.

    CAS  Google Scholar 

  84. 84

    Meyer, C. et al. μ1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors. EMBO J. 19, 2193–2203 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85

    Meyer, C., Eskelinen, E. L., Guruprasad, M. R., von Figura, K. & Schu, P. μ1A deficiency induces a profound increase in MPR300/IGF-II receptor internalization rate. J. Cell Sci. 114, 4469–4476 (2001). References 84 and 85 were the first studies to implicate AP1 in retrograde trafficking of MPRs from endosomes to the trans -Golgi network.

    CAS  Google Scholar 

  86. 86

    Wan, L. et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 94, 205–216 (1998).

    CAS  Google Scholar 

  87. 87

    Crump, C. M. et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J. 20, 2191–2201 (2001). This reference cites the first evidence in support of PACS-1/AP1-mediated retrograde transport of MPRs from early endosomes to the trans -Golgi network.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. 88

    Tikkanen, R. et al. The dileucine motif within the tail of the MPR46 is required for sorting of the receptor in endosomes. Traffic 1, 631–640 (2000).

    CAS  Google Scholar 

  89. 89

    Wasiak, S. et al. Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics. J. Cell Biol. 158, 855–862 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  90. 90

    Jadot, M., Canfield, W. M., Gregory, W. & Kornfeld, S. Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor. J. Biol. Chem. 267, 11069–11077 (1992).

    CAS  Google Scholar 

  91. 91

    Johnson, K. F., Chan, W. & Kornfeld, S. Cation-dependent mannose 6-phosphate receptor contains two internalization signals in its cytoplasmic domain. Proc. Natl Acad. Sci. USA 87, 10010–10014 (1990).

    CAS  Google Scholar 

  92. 92

    Denzer, K., Weber, B., Hille-Rehfeld, A., von Figura, K. & Pohlmann, R. Identification of three internalization sequences in the cytoplasmic tail of the 46 kDa mannose 6-phosphate receptor. Biochem. J. 326, 497–505 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. 93

    Storch, S. & Braulke, T. Multiple C-terminal motifs of the 46-kDa mannose 6-phosphate receptor tail contribute to efficient binding of medium chains of AP-2 and AP-3. J. Biol. Chem. 276, 4298–4303 (2001).

    CAS  Google Scholar 

  94. 94

    Ludwig, T. et al. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in IGF2 and IGF1R null backgrounds. Dev. Biol. 177, 517–535 (1996).

    CAS  Google Scholar 

  95. 95

    Wang, Z. Q., Fung, M. R., Barlow, D. P. & Wagner, E. F. Regulation of embryonic growth and lysosomal targeting by the imprinted IGF2/MPR gene. Nature 372, 464–467 (1994).

    CAS  Google Scholar 

  96. 96

    Lau, M. M. et al. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev. 8, 2953–2963 (1994).

    CAS  Google Scholar 

  97. 97

    Ikezu, T., Okamoto, T., Giambarella, U., Yokota, T. & Nishimoto, I. In vivo coupling of insulin-like growth factor II/mannose 6-phosphate receptor to heteromeric G proteins. Distinct roles of cytoplasmic domains and signal sequestration by the receptor. J. Biol. Chem. 270, 29224–29228 (1995).

    CAS  Google Scholar 

  98. 98

    Zhang, Q. et al. Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose 6-phosphate receptor promotes exocytosis in insulin-secreting cells. Proc. Natl Acad. Sci. USA 94, 6232–6237 (1997).

    CAS  Google Scholar 

  99. 99

    McKinnon, T., Chakraborty, C., Gleeson, L. M., Chidiac, P. & Lala, P. K. Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK. J. Clin. Endocrinol. Metab. 86, 3665–3674 (2001).

    CAS  Google Scholar 

  100. 100

    Groskopf, J. C., Syu, L. J., Saltiel, A. R. & Linzer, D. I. Proliferin induces endothelial cell chemotaxis through a G protein-coupled, mitogen-activated protein kinase-dependent pathway. Endocrinology 138, 2835–2840 (1997).

    CAS  Google Scholar 

  101. 101

    Minniti, C. P. et al. The insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor mediates IGF-II-induced motility in human rhabdomyosarcoma cells. J. Biol. Chem. 267, 9000–9004 (1992).

    CAS  Google Scholar 

  102. 102

    Tsuruta, J. K., Eddy, E. M. & O'Brien, D. A. Insulin-like growth factor-II/cation-independent mannose 6-phosphate receptor mediates paracrine interactions during spermatogonial development. Biol. Reprod. 63, 1006–1013 (2000).

    CAS  Google Scholar 

  103. 103

    Ikushima, H. et al. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc. Natl Acad. Sci. USA 97, 8439–8444 (2000).

    CAS  Google Scholar 

  104. 104

    Nishimoto, I. The IGF-II receptor system: a G protein-linked mechanism. Mol. Reprod. Dev. 35, 398–406 (1993).

    CAS  Google Scholar 

  105. 105

    Frasca, F. et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol. Cell. Biol. 19, 3278–3288 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  106. 106

    Korner, C., Nurnberg, B., Uhde, M. & Braulke, T. Mannose 6-phosphate/insulin-like growth factor II receptor fails to interact with G-proteins. Analysis of mutant cytoplasmic receptor domains. J. Biol. Chem. 270, 287–295 (1995).

    CAS  Google Scholar 

  107. 107

    Ikushima, H. et al. Soluble CD26/dipeptidyl peptidase IV enhances transendothelial migration via its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cell. Immunol 215, 106–110 (2002).

    CAS  Google Scholar 

  108. 108

    Purchio, A. F. et al. Identification of mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-β1 precursor. J. Biol. Chem. 263, 14211–14215 (1988).

    CAS  Google Scholar 

  109. 109

    Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).

    CAS  Google Scholar 

  110. 110

    Dennis, P. A. & Rifkin, D. B. Cellular activation of latent transforming growth factor β requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor. Proc. Natl Acad. Sci. USA 88, 580–584 (1991). This work showed for the first time that the CI-MPR plays a significant role in activation of the latent form of TGF-β1.

    CAS  Google Scholar 

  111. 111

    Nunes, I., Shapiro, R. L. & Rifkin, D. B. Characterization of latent TGF-β activation by murine peritoneal macrophages. J. Immunol. 155, 1450–1459 (1995).

    CAS  Google Scholar 

  112. 112

    Godar, S. et al. M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-β1. Eur. J. Immunol. 29, 1004–1013 (1999).

    CAS  Google Scholar 

  113. 113

    Ghahary, A. Tredget, E. E. & Shen, Q. Insulin-like growth factor-II/mannose 6 phosphate receptors facilitate the matrix effects of latent transforming growth factor-β1 released from genetically modified keratinocytes in a fibroblast/keratinocyte co-culture system. J. Cell Physiol. 180, 61–70 (1999).

    CAS  Google Scholar 

  114. 114

    Chen, A., Davis, B. H., Sitrin, M. D., Brasitus, T. A. & Bissonnette, M. Transforming growth factor-β1 signaling contributes to Caco cell growth inhibition induced by 1,25(OH)2D3. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G864–G874 (2002).

    CAS  Google Scholar 

  115. 115

    Leksa, V. et al. The N-terminus of mannose 6-phosphate/insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration. J. Biol. Chem. 277, 40575–40582 (2002).

    CAS  Google Scholar 

  116. 116

    Nykjaer, A. et al. Mannose 6-phosphate /insulin-like growth factor–II receptor targets the urokinase receptor to lysosomes via a novel binding interaction. J. Cell Biol. 141, 815–828 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. 117

    Kang, J. X., Bell, J., Beard, R. L. & Chandraratna, R. A. Mannose 6-phosphate/insulin-like growth factor II receptor mediates the growth-inhibitory effects of retinoids. Cell Growth Differ. 10, 591–600 (1999).

    CAS  Google Scholar 

  118. 118

    Zaina, S. & Squire, S. The soluble type 2 insulin-like growth factor (IGF-II) receptor reduces organ size by IGF-II-mediated and IGF-II-independent mechanisms. J. Biol. Chem. 273, 28610–28616 (1998).

    CAS  Google Scholar 

  119. 119

    O'Gorman, D. B., Weiss, J., Hettiaratchi, A., Firth, S. M. & Scott, C. D. Insulin-like growth factor-II/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo. Endocrinology 143, 4287–4294 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  120. 120

    DeSouza, A. T., Hankins, G. R., Washington, M. K., Orton, T. C. & Jirtle, R. L. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nature Genet. 11, 447–449 (1995). The first evidence that CI-MPR is mutated in human cancers.

    CAS  Google Scholar 

  121. 121

    Yamada, T., DeSouza, A. T., Finkelstein, S. & Jirtle, R. L. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Proc. Natl Acad. Sci. USA 94, 10351–10355 (1997).

    CAS  Google Scholar 

  122. 122

    Oka, Y. et al. M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology 35, 1153–1163 (2002).

    CAS  Google Scholar 

  123. 123

    Hankins, G. R. et al. M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12, 2003–2009 (1996).

    CAS  Google Scholar 

  124. 124

    Chappell, S. A., Walsh, T., Walker, R. A. & Shaw, J. A. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor gene correlates with poor differentiation in early breast carcinomas. Br. J. Cancer 76, 1558–1561 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  125. 125

    Kong, F. M., Anscher, M. S., Washington, M. K., Killian, J. K. & Jirtle, R. L. M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Oncogene 19, 1572–1578 (2000).

    CAS  Google Scholar 

  126. 126

    Rey, J. M., Theillet, C., Brouillet, J. P. & Rochefort, H. Stable amino-acid sequence of the mannose-6-phosphate/insulin-like growth-factor-II receptor in ovarian carcinomas with loss of heterozygosity and in breast-cancer cell lines. Int. J. Cancer 85, 466–473 (2000).

    CAS  Google Scholar 

  127. 127

    Leboulleux, S., Gaston, V., Boulle, N., LeBouc, Y. & Gicquel, C. Loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor receptor locus: a frequent but late event in adrenocortical tumorigenesis. Eur. J. Endocrinol. 144, 163–168 (2001).

    CAS  Google Scholar 

  128. 128

    Gemma, A. et al. Mutation analysis of the gene encoding the human mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) in human cell lines resistant to growth inhibition by transforming growth factor β1 (TGF-β1). Lung Cancer 30, 91–98 (2000).

    CAS  Google Scholar 

  129. 129

    Byrd, J. C., Devi, G. R., DeSouza, A. T., Jirtle, R. L. & MacDonald, R. G. Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations. J. Biol. Chem. 274, 24408–24416 (1999).

    CAS  Google Scholar 

  130. 130

    Devi, G. R., DeSouza, A. T., Byrd, J. C., Jirtle, R. L. & MacDonald, R. G. Altered ligand binding by insulin-like growth factor II/mannose 6-phosphate receptors bearing missense mutations in human cancers. Cancer Res. 59, 4314–4319 (1999). References 128–130 show that cancer-associated mutations in the CI-MPR impair receptor function.

    CAS  Google Scholar 

  131. 131

    Collins, B. M., McCoy, A. J., Kent, H. M., Evans, P. R. & Owen, D. J. Molecular architecture and functional model of the endocytic AP 2 complex. Cell 109, 523–535 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  132. 132

    Ricotta, D., Conner, S. D., Schmid, S. L., von Figura, K. & Honing, S. Phosphorylation of the AP2 μ-subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J. Cell Biol. 156, 791–795 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. 133

    DaCosta, S. A., Schumaker, L. M. & Ellis, M. J. Mannose 6-phosphate/insulin-like growth factor 2 receptor, a bona fide tumor suppressor gene or just a promising candidate? J. Mammary Gland Biol. Neoplasia 5, 85–94 (2000).

    CAS  Google Scholar 

  134. 134

    Motyka, B. et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103, 491–500 (2000).

    CAS  Google Scholar 

Download references


We thank C. Byrd, D. Tollefsen, K. Howell, R. Kornfeld and members of the Kornfeld laboratory for their critical reading of the manuscript and helpful suggestions.

Author information



Corresponding author

Correspondence to Stuart Kornfeld.

Related links

Related links










granzyme B

IGF-binding protein 5





syntaxin 6

syntaxin 13







Heterotetrameric protein complexes that connect molecules on membranes and structural coat proteins, for example clathrin. AP1 mediates cargo transport between the trans-Golgi network (TGN) and endosomes through the generation of clathrin-coated carriers.


These are membrane evaginations that have assembled clathrin on their surface. The forming vesicles bud off and function as carriers for sorted proteins.


A multidomain, cytosolic protein with an amino-terminal VHS domain that binds cargo, followed by a coiled-coil GAT domain that mediates membrane recruitment through ARF; a variable hinge segment that contains clathrin- and AP1-binding regions; and a carboxy-terminal ear domain, which recruits accessory proteins and has homology to the γ-appendage. These molecules have recently been implicated in the sorting of MPRs at the TGN.


An approximately 150-residue domain whose name is derived from its presence in VPS-27, Hrs and STAM. It is found at the amino termini of proteins that are associated with endocytosis and/or vesicular trafficking.


(casein kinase 2). A phosphorylation site that is characterized by the presence of phosphoacceptor residues (S/T) that are flanked by clusters of negatively charged amino acids, the residue at position n+3 being one of the following: an aspartate, glutamate, phosphoserine or phosphothreonine. The minimum concensus sequence is S/T XX D/E/pS/pT.


A general method for the three-dimensional reconstruction of single, transparent objects from a series of projection images (that is, from a tilt series) that are recorded with a transmission electron microscope.


(heat shock cognate protein of 70kDa). Proteins of this chaperone family are involved in a range of cellular processes, such as protein folding, translocation across membranes and the assembly or disassembly of protein complexes.


A neuronal protein that contains a clathrin-binding site and a carboxy-terminal J-domain that interacts with and stimulates the dormant ATPase of the chaperone Hsc70.


(kinesin family 13A). A novel plus-end-directed microtubule-dependent motor protein that associates with mannose 6-phosphate receptor (MPR)-containing carriers through the β1-subunit of AP1.


Monomeric small GTPases which, along with their effectors, mediate the first specific event during membrane fusion; that is, tethering of an incoming vesicle to the correct target organelle.


(soluble N-ethyl-maleimide-sensitive (NSF) attachment protein receptors). Proteins that are implicated in mediating most intracellular membrane-fusion events by interacting with each other to generate the driving force needed to fuse lipid bilayers.


(tail-interacting protein, 47 kDa). A novel hydrophilic, cytosolic protein of 47 kDa that binds directly to cytoplasmic tails of both the cation-independent and cation-dependent MPRs and is involved in sorting at the endosomes.


(phosphofurin acidic cluster-sorting protein). A cytosolic linker molecule that connects proteins such as furin, HIV virus type-1 (HIV-1) Nef and the CI-MPR, through their acidic-cluster sorting motifs, to adaptors (AP1 and AP3, but not AP2).


A cell that is located in the male gonads and provides nourishment to sperm.


A loss of either the maternal or paternal allele of a gene. This is often a molecular marker of a tumour-suppressor gene locus.


(MSI). Alterations of the length of simple repetitive genomic sequences. In tumours it is an indication that there have probably been mutations in genes encoding proteins that are involved in DNA repair.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ghosh, P., Dahms, N. & Kornfeld, S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4, 202–213 (2003).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing