igf type 2 receptor


Summary: A receptor that is specific for IGF-II and mannose-6-phosphate. The receptor is a 250-kDa single chain polypeptide which is unrelated in structure to the type 1 IGF receptor (RECEPTOR, IGF TYPE 1) and does not have a tyrosine kinase domain.

Top Publications

  1. Karlsson K, Carlsson S. Sorting of lysosomal membrane glycoproteins lamp-1 and lamp-2 into vesicles distinct from mannose 6-phosphate receptor/gamma-adaptin vesicles at the trans-Golgi network. J Biol Chem. 1998;273:18966-73 pubmed
    ..The results indicate that membrane proteins containing tyrosine-based motifs for sorting at the TGN are segregated from clathrin-coated vesicles containing MPRs. ..
  2. Ghosh P, Griffith J, Geuze H, Kornfeld S. Mammalian GGAs act together to sort mannose 6-phosphate receptors. J Cell Biol. 2003;163:755-66 pubmed
    ..The morphology of the TGN was also altered. These findings indicate that the three mammalian GGAs cooperate to sort cargo and are required for maintenance of TGN structure...
  3. Ghosh P, Dahms N, Kornfeld S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol. 2003;4:202-12 pubmed
    ..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. ..
  4. Zavras A, Pitiphat W, Wu T, Cartsos V, Lam A, Douglass C, et al. Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans. Cancer Res. 2003;63:296-7 pubmed
    ..7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer. ..
  5. Chen Z, Ge Y, Landman N, Kang J. Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells. BMC Cancer. 2002;2:18 pubmed
    ..This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth. ..
  6. Hanna J, Carroll K, Pfeffer S. Identification of residues in TIP47 essential for Rab9 binding. Proc Natl Acad Sci U S A. 2002;99:7450-4 pubmed
    ..These experiments reveal distinct binding domains for the Rab9 GTPase and MPR cytoplasmic domains in the cargo selection protein TIP47. ..
  7. Pérez Victoria F, Mardones G, Bonifacino J. Requirement of the human GARP complex for mannose 6-phosphate-receptor-dependent sorting of cathepsin D to lysosomes. Mol Biol Cell. 2008;19:2350-62 pubmed publisher
    ..We also report that a Vps54 mutant protein in the Wobbler mouse strain is active in retrograde transport, thus explaining the viability of these mutant mice. ..
  8. Qian M, Sleat D, Zheng H, Moore D, Lobel P. Proteomics analysis of serum from mutant mice reveals lysosomal proteins selectively transported by each of the two mannose 6-phosphate receptors. Mol Cell Proteomics. 2008;7:58-70 pubmed
    ..This study provides a comparison of different quantitative mass spectrometric approaches and provides the first report of proteins whose cellular targeting appears to be MPR-selective under physiological conditions. ..
  9. Scott G, Fei H, Thomas L, Medigeshi G, Thomas G. A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. EMBO J. 2006;25:4423-35 pubmed
    ..Our results identify a CK2-controlled cascade regulating hydrolase trafficking and sorting of itinerant proteins in the TGN/endosomal system. ..

More Information


  1. Zaccheo O, Prince S, Miller D, Williams C, Kemp C, Brown J, et al. Kinetics of insulin-like growth factor II (IGF-II) interaction with domain 11 of the human IGF-II/mannose 6-phosphate receptor: function of CD and AB loop solvent-exposed residues. J Mol Biol. 2006;359:403-21 pubmed
    ..These findings have implications for the molecular architecture and evolution of the domain 11 IGF-II-binding site, and the potential interactions with other domains of IGF2R. ..
  2. Arighi C, Hartnell L, Aguilar R, Haft C, Bonifacino J. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J Cell Biol. 2004;165:123-33 pubmed
    ..These observations indicate that retromer prevents the delivery of the CI-MPR to lysosomes, probably by sequestration into endosome-derived tubules from where the receptor returns to the TGN. ..
  3. Saint Pol A, Yélamos B, Amessou M, Mills I, Dugast M, Tenza D, et al. Clathrin adaptor epsinR is required for retrograde sorting on early endosomal membranes. Dev Cell. 2004;6:525-38 pubmed
    ..In conclusion, our work reveals the existence of clathrin-independent and -dependent transport steps in the retrograde route, and establishes a function for clathrin and epsinR at the endosome-TGN interface...
  4. Lin S, Mallet W, Huang A, Maxfield F. Endocytosed cation-independent mannose 6-phosphate receptor traffics via the endocytic recycling compartment en route to the trans-Golgi network and a subpopulation of late endosomes. Mol Biol Cell. 2004;15:721-33 pubmed
    ..These data demonstrate that CI-MPR takes a complex route that involves multiple sorting steps in both early and late endosomes. ..
  5. Hancock M, Yammani R, Dahms N. Localization of the carbohydrate recognition sites of the insulin-like growth factor II/mannose 6-phosphate receptor to domains 3 and 9 of the extracytoplasmic region. J Biol Chem. 2002;277:47205-12 pubmed
  6. Waguri S, Tomiyama Y, Ikeda H, Hida T, Sakai N, Taniike M, et al. The luminal domain participates in the endosomal trafficking of the cation-independent mannose 6-phosphate receptor. Exp Cell Res. 2006;312:4090-107 pubmed
  7. Wylie A, Pulford D, McVie Wylie A, Waterland R, Evans H, Chen Y, et al. Tissue-specific inactivation of murine M6P/IGF2R. Am J Pathol. 2003;162:321-8 pubmed
  8. 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. 2002;297:1700-3 pubmed
    ..MPRs that are defective in binding to GGAs are poorly incorporated into AP-1-containing clathrin-coated vesicles. Thus, the GGAs and AP-1 interact to package MPRs into AP-1-containing coated vesicles. ..
  9. Wang Y, Tai G, Lu L, Johannes L, Hong W, Tang B. Trans-Golgi network syntaxin 10 functions distinctly from syntaxins 6 and 16. Mol Membr Biol. 2005;22:313-25 pubmed
  10. Puertollano R, Bonifacino J. Interactions of GGA3 with the ubiquitin sorting machinery. Nat Cell Biol. 2004;6:244-51 pubmed
    ..The VHS and GAT domains of GGA3 are responsible for this binding, as well as for interactions with TSG101, a component of the ubiquitin-dependent sorting machinery. Thus, GGAs may have additional roles in sorting of ubiquitinated cargo. ..
  11. Kaku K, Osada H, Seki K, Sekiya S. Insulin-like growth factor 2 (IGF2) and IGF2 receptor gene variants are associated with fetal growth. Acta Paediatr. 2007;96:363-7 pubmed
    ..There was also a significant difference in birth weight among the three neonatal c.901C > G genotypes of the IGF2R gene; CC, CG and GG. These findings indicate that both IGF2 and IGF2R gene variants are associated with fetal growth. ..
  12. Ghosh P, Kornfeld S. The GGA proteins: key players in protein sorting at the trans-Golgi network. Eur J Cell Biol. 2004;83:257-62 pubmed
    ..This review covers the recent structural and cell biological studies that have provided mechanistic insights into the function of the GGAs in mannose 6-phosphate receptor trafficking. ..
  13. Carlton J, Bujny M, Peter B, Oorschot V, Rutherford A, Mellor H, et al. Sorting nexin-1 mediates tubular endosome-to-TGN transport through coincidence sensing of high- curvature membranes and 3-phosphoinositides. Curr Biol. 2004;14:1791-800 pubmed
  14. Sleat D, Lackland H, Wang Y, Sohar I, Xiao G, Li H, et al. The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of multiple isoforms of many soluble lysosomal proteins. Proteomics. 2005;5:1520-32 pubmed
    ..We found that the human brain Man6-P-containing lysosomal proteome is highly complex and contains more proteins with a much greater number of individual isoforms than found in previous studies of Man6-P glycoproteomes. ..
  15. Williams C, Rezgui D, Prince S, Zaccheo O, Foulstone E, Forbes B, et al. Structural insights into the interaction of insulin-like growth factor 2 with IGF2R domain 11. Structure. 2007;15:1065-78 pubmed
    ..The models reveal that the molecular interaction is driven by critical hydrophobic residues on IGF2 and IGF2R, while a ring of flexible, charged residues on IGF2R may modulate binding. ..
  16. Lefrancois S, Zeng J, Hassan A, Canuel M, Morales C. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J. 2003;22:6430-7 pubmed
    ..In conclusion, our results show that the trafficking of SAPs is dependent on sortilin, demonstrating a novel lysosomal trafficking. ..
  17. Kotsinas A, Evangelou K, Sideridou M, Kotzamanis G, Constantinides C, Zavras A, et al. The 3' UTR IGF2R-A2/B2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer. Cancer Lett. 2008;259:177-85 pubmed
    ..In conclusion, the IGF2R-A2/B2 variant probably provides a selective advantage for NSCLC progression through increased tumor growth. ..
  18. Brown J, Delaine C, Zaccheo O, Siebold C, Gilbert R, van Boxel G, et al. Structure and functional analysis of the IGF-II/IGF2R interaction. EMBO J. 2008;27:265-76 pubmed
    ..Mutagenesis analyses confirm this IGF-II 'binding-hotspot', revealing that IGF-binding proteins and IGF2R have converged on the same high-affinity site. ..
  19. Carlton J, Bujny M, Peter B, Oorschot V, Rutherford A, Arkell R, et al. Sorting nexin-2 is associated with tubular elements of the early endosome, but is not essential for retromer-mediated endosome-to-TGN transport. J Cell Sci. 2005;118:4527-39 pubmed
  20. Harper J, Burns J, Foulstone E, Pignatelli M, Zaina S, Hassan A. Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting. Cancer Res. 2006;66:1940-8 pubmed
    ..This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand-specific therapeutic intervention in colorectal cancer. ..
  21. Bonifacino J. The GGA proteins: adaptors on the move. Nat Rev Mol Cell Biol. 2004;5:23-32 pubmed
  22. Waguri S, DeWitte F, Le Borgne R, Rouille Y, Uchiyama Y, Dubremetz J, et al. Visualization of TGN to endosome trafficking through fluorescently labeled MPR and AP-1 in living cells. Mol Biol Cell. 2003;14:142-55 pubmed
  23. Dahms N, Hancock M. P-type lectins. Biochim Biophys Acta. 2002;1572:317-40 pubmed
    ..This review provides a current view on the structures, functions, and medical relevance of the P-type lectins. ..
  24. Ganley I, Pfeffer S. Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells. J Biol Chem. 2006;281:17890-9 pubmed
    ..We conclude that cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking...
  25. Reddy J, Burguete A, Sridevi K, Ganley I, Nottingham R, Pfeffer S. A functional role for the GCC185 golgin in mannose 6-phosphate receptor recycling. Mol Biol Cell. 2006;17:4353-63 pubmed
    ..These data assign a specific pathway to an interesting, TGN-localized protein and suggest that GCC185 may participate in the docking of late endosome-derived, Rab9-bearing transport vesicles at the TGN...
  26. Oka Y, Waterland R, Killian J, Nolan C, Jang H, Tohara K, et al. M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology. 2002;35:1153-63 pubmed
    ..Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis. ..
  27. Rojas R, Kametaka S, Haft C, Bonifacino J. Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Mol Cell Biol. 2007;27:1112-24 pubmed
  28. Petry C, Ong K, Wingate D, Brown J, Scott C, Jones E, et al. Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height. Growth Horm IGF Res. 2005;15:363-8 pubmed
    ..There were no detectable differences in weights at 7 years. Allelic variation in the gly1619arg SNP of the IGF2R gene is associated with disparity in childhood stature which could reflect altered binding of IGF-II to its receptor. ..
  29. Kreiling J, Byrd J, MacDonald R. Domain interactions of the mannose 6-phosphate/insulin-like growth factor II receptor. J Biol Chem. 2005;280:21067-77 pubmed
    ..We conclude that there is no finite M6P/IGF2R dimerization domain, but rather that interactions between dimer partners occur all along the extracytoplasmic region of the receptor. ..
  30. Kato Y, Misra S, Puertollano R, Hurley J, Bonifacino J. Phosphoregulation of sorting signal-VHS domain interactions by a direct electrostatic mechanism. Nat Struct Biol. 2002;9:532-6 pubmed
  31. Seaman M. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol. 2004;165:111-22 pubmed
    ..The data presented here support the hypothesis that retromer performs a selective function in endosome-to-Golgi transport, mediating retrieval of the CI-MPR, but not furin. ..
  32. McCann J, Xu Y, Frechette R, Guazzarotti L, Polychronakos C. The insulin-like growth factor-II receptor gene is associated with type 1 diabetes: evidence of a maternal effect. J Clin Endocrinol Metab. 2004;89:5700-6 pubmed
    ..Thus, we present evidence that maternal alleles at an IGF2R polymorphism are associated with T1D. It is thus possible that at some tissue or developmental stage not yet examined, IGF2R is universally imprinted. ..
  33. Meyer C, Eskelinen E, Guruprasad M, Von Figura K, Schu P. Mu 1A deficiency induces a profound increase in MPR300/IGF-II receptor internalization rate. J Cell Sci. 2001;114:4469-76 pubmed
    ..Thus AP-1-mediated transport of MPR300 from endosomes to the TGN controls indirectly the recycling rate of the receptor between the plasma membrane and endosomes. ..
  34. Zhu Y, Doray B, Poussu A, Lehto V, Kornfeld S. Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Science. 2001;292:1716-8 pubmed
    ..The hinge domain of GGA2 bound clathrin, suggesting that GGA2 could be a link between cargo molecules and clathrin-coated vesicle assembly. Thus, GGA2 binding to the CI-MPR is important for lysosomal enzyme targeting. ..
  35. Klumperman J, Kuliawat R, Griffith J, Geuze H, 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. 1998;141:359-71 pubmed
    ..Thus, we hypothesize that during secretory granule maturation, MPR-ligand complexes and syntaxin 6 are removed from IGs by AP-1/clathrin-coated vesicles, and then delivered to endosomes. ..
  36. Krise J, Sincock P, Orsel J, Pfeffer S. Quantitative analysis of TIP47-receptor cytoplasmic domain interactions: implications for endosome-to-trans Golgi network trafficking. J Biol Chem. 2000;275:25188-93 pubmed
    ..Moreover, our data suggest unexpectedly that furin, TGN38, and carboxypeptidase D may use a distinct vesicular carrier and perhaps a distinct route for transport between endosomes and the trans Golgi network. ..
  37. Young L, Fernandes K, McEvoy T, Butterwith S, Gutierrez C, Carolan C, et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet. 2001;27:153-4 pubmed
    ..This highlights the potential benefits of epigenetic diagnostic screening in developing embryo procedures. ..
  38. Brown J, Esnouf R, Jones M, Linnell J, Harlos K, Hassan A, et al. Structure of a functional IGF2R fragment determined from the anomalous scattering of sulfur. EMBO J. 2002;21:1054-62 pubmed
    ..The structure factors and coordinates of IGF2R domain 11 have been deposited in the Protein Data Bank (accession codes 1GP0 and 1GP3). ..
  39. Orsel J, Sincock P, Krise J, Pfeffer S. Recognition of the 300-kDa mannose 6-phosphate receptor cytoplasmic domain by 47-kDa tail-interacting protein. Proc Natl Acad Sci U S A. 2000;97:9047-51 pubmed
    ..Although crystallography will be needed to define the precise interaction interface, these data provide an initial structural basis for TIP47-CI-MPR association. ..
  40. Killian J, Oka Y, Jang H, Fu X, Waterland R, Sohda T, et al. Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations. Hum Mutat. 2001;18:25-31 pubmed
    ..Three identified amino-acid variants in the M6P/IGF2R ligand-binding domains may be under selection in humans. ..
  41. McKinnon T, Chakraborty C, Gleeson L, Chidiac P, Lala P. 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. 2001;86:3665-74 pubmed
    ..We found that the extravillous trophoblast cells expressed an abundance of IGF type 2 receptor as detected by immunostaining and Western blots, and recombinant human IGF-II promoted their migration in a ..
  42. Misra S, Puertollano R, Kato Y, Bonifacino J, Hurley J. Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains. Nature. 2002;415:933-7 pubmed
    ..The rigid spatial alignment of the three binding subsites leads to high specificity. ..
  43. Shiba T, Takatsu H, Nogi T, Matsugaki N, Kawasaki M, Igarashi N, et al. Structural basis for recognition of acidic-cluster dileucine sequence by GGA1. Nature. 2002;415:937-41 pubmed
    ..This recognition mechanism provides the basis for regulation of protein transport from the TGN to endosomes/lysosomes, which is shared by sortilin and low-density lipoprotein receptor-related protein. ..
  44. Dittmer F, Ulbrich E, Hafner A, Schmahl W, Meister T, Pohlmann R, et al. Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific. J Cell Sci. 1999;112 ( Pt 10):1591-7 pubmed
  45. Puertollano R, Aguilar R, Gorshkova I, Crouch R, Bonifacino J. Sorting of mannose 6-phosphate receptors mediated by the GGAs. Science. 2001;292:1712-6 pubmed
    ..A dominant-negative GGA mutant blocked exit of the receptors from the trans-Golgi network. Thus, the GGAs appear to mediate sorting of the mannose 6-phosphate receptors at the trans-Golgi network. ..
  46. Linnell J, Groeger G, Hassan A. 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. 2001;276:23986-91 pubmed
    ..0-7.4. The constructs behaved differently in response to pH and in recovery after low pH exposure, suggesting that pH stability of the extracellular domains depends on domains other than 10-13. ..
  47. Osipo C, Dorman S, Frankfater A. Loss of insulin-like growth factor II receptor expression promotes growth in cancer by increasing intracellular signaling from both IGF-I and insulin receptors. Exp Cell Res. 2001;264:388-96 pubmed
    ..The results directly demonstrate that down regulation of the IGF-IIR promotes the growth of transformed D9 cells by sustaining IGF-II, which binds to and activates IGF-IR and insulin receptor to increase intracellular growth signals. ..
  48. Carroll K, Hanna J, Simon I, Krise J, Barbero P, Pfeffer S. Role of Rab9 GTPase in facilitating receptor recruitment by TIP47. Science. 2001;292:1373-6 pubmed
    ..Thus, a cytosolic cargo selection device may be selectively recruited onto a specific organelle, and vesicle budding might be coupled to the presence of an active Rab GTPase. ..
  49. Yandell C, Dunbar A, Wheldrake J, Upton Z. The kangaroo cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II with low affinity. J Biol Chem. 1999;274:27076-82 pubmed
    ..Thus, the acquisition of a high-affinity binding site for regulating IGF-II appears to be a recent event specific to the eutherian lineage. ..
  50. Killian J, Nolan C, Wylie A, Li T, Vu T, Hoffman A, et al. Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary. Hum Mol Genet. 2001;10:1721-8 pubmed
    ..Moreover, the divergent evolution of M6P/IGF2R imprinting predicts that the success of in vitro embryo procedures such as cloning may be species dependent...
  51. Motyka B, Korbutt G, Pinkoski M, Heibein J, Caputo A, Hobman M, 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. 2000;103:491-500 pubmed
    ..These results suggest a novel target for immunotherapy and a potential mechanism used by tumors for immune evasion. ..
  52. Takatsu H, Katoh Y, Shiba Y, Nakayama K. Golgi-localizing, gamma-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. 2001;276:28541-5 pubmed
    ..These results indicate that GGA proteins regulate the localization to or exit from the TGN of the sorting receptors. ..
  53. Crump C, Xiang Y, Thomas L, Gu F, Austin C, Tooze S, et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J. 2001;20:2191-201 pubmed
    ..These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis. ..