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Gene Review

IGF2R  -  insulin-like growth factor 2 receptor

Homo sapiens

Synonyms: 300 kDa mannose 6-phosphate receptor, CD222, CI Man-6-P receptor, CI-MPR, CIMPR, ...
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Disease relevance of IGF2R


High impact information on IGF2R


Chemical compound and disease context of IGF2R


Biological context of IGF2R

  • Structural analysis identifies the putative IGF-II binding site at one end of the beta-barrel whilst crystal lattice contacts suggest a model for the full-length IGF2R extracellular region [14].
  • Thus, dimerization of glycosylated CREG likely presents a bivalent ligand for the M6P/IGF2R [15].
  • At the IGF2R DMR, we observed more variability in the allelic methylation ratios over time but also observed familial clustering of abnormal methylation ratios [16].
  • The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) forms oligomeric structures important for optimal function in binding and internalization of Man-6-P-bearing extracellular ligands as well as lysosomal biogenesis and growth regulation [17].
  • The M6P/IGF2R is a tumor suppressor that functions to control cell growth through interactions with multiple ligands [18].

Anatomical context of IGF2R

  • Consistent with the absence of M6P/IGF2R, SCC-VII cells lack dense lysosomes, with the bulk of intracellular acid hydrolases residing in late endosomes/ prelysosomes [19].
  • IGF2R, with multiple functions in both normal growth and cancer, was investigated here as a possible USF target in both nontumorigenic and tumorigenic breast cell lines [20].
  • These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A [20].
  • Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome [21].
  • Analysis of IGF2R expression and function suggested that decreased IGF2R expression could partly account for the increased growth of lymph node carcinoma of the prostate (LNCaP) human prostate cancer cells observed with increasing passage in culture [22].

Associations of IGF2R with chemical compounds

  • Western blotting analysis revealed that SCC-VII cells are deficient in the 300 kDa mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R), a tumor suppressor with a central role in the intracellular transport of lysosomal enzymes [19].
  • The M6P/IGF2R functions in the inactivation of the mitogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta [2].
  • We have mutated residues A54 and L55 of IGF-II in the second A domain helix to arginine (found in the corresponding positions of IGF-I) and measured IGF2R binding [23].
  • The Type-2 insulin-like growth factor receptor (IGF2R) is a ubiquitously expressed integral glycoprotein with a molecular mass of 300 kDa [24].
  • In addition, suramin inhibited cross-linking of ¿125I¿IGF-II to the type 1 IGF receptor (IGF1R) and type 2 IGF receptor (IGF2R) [25].

Physical interactions of IGF2R

  • The remaining allele in 6/11 (55%) LOH patients contained mutations in either the mannose 6-phosphate or the IGF2 binding domain of the M6P/IGF2R [5].
  • M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1 [26].
  • Thus, analysis of a structure-based mutant of CREG revealed that binding to M6P/IGF2R, while necessary, is not sufficient for CREG-induced growth suppression [15].
  • Coimmunoprecipitation assays revealed that soluble recombinant uPAR (suPAR) bound the Man-6-P/IGF2R at two distinct sites, one localized to the amino-terminal end of the Man-6-P/IGF2R extracytoplasmic domain (repeats 1-3) and the other to the more carboxyl-terminal end (repeats 7-9) [27].
  • Thus, GGA2 binding to the CI-MPR is important for lysosomal enzyme targeting [28].

Regulatory relationships of IGF2R

  • A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth [10].
  • These studies reveal that CREG inhibits cell growth dependent on the M6P/IGF2R and suggest that interactions between CREG and a well-characterized tumor suppressor may contribute to regulation of proliferation and differentiation in multiple lineages [18].
  • A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking [29].
  • An immunoglobulin (no. 3637) directed against the rat IGF-II receptor blocked the degradation of [125I]IGF-II added to C6 glial cells, presumably by blocking receptor-mediated internalization [30].

Other interactions of IGF2R


Analytical, diagnostic and therapeutic context of IGF2R


  1. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. De Souza, A.T., Hankins, G.R., Washington, M.K., Orton, T.C., Jirtle, R.L. Nat. Genet. (1995) [Pubmed]
  2. Imprinted genes in liver carcinogenesis. De Souza, A.T., Yamada, T., Mills, J.J., Jirtle, R.L. FASEB J. (1997) [Pubmed]
  3. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Kaplan, P.J., Mohan, S., Cohen, P., Foster, B.A., Greenberg, N.M. Cancer Res. (1999) [Pubmed]
  4. Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan. Wada, I., Kanada, H., Nomura, K., Kato, Y., Machinami, R., Kitagawa, T. Hepatology (1999) [Pubmed]
  5. M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Kong, F.M., Anscher, M.S., Washington, M.K., Killian, J.K., Jirtle, R.L. Oncogene (2000) [Pubmed]
  6. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Motyka, B., Korbutt, G., Pinkoski, M.J., Heibein, J.A., Caputo, A., Hobman, M., Barry, M., Shostak, I., Sawchuk, T., Holmes, C.F., Gauldie, J., Bleackley, R.C. Cell (2000) [Pubmed]
  7. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Souza, R.F., Appel, R., Yin, J., Wang, S., Smolinski, K.N., Abraham, J.M., Zou, T.T., Shi, Y.Q., Lei, J., Cottrell, J., Cymes, K., Biden, K., Simms, L., Leggett, B., Lynch, P.M., Frazier, M., Powell, S.M., Harpaz, N., Sugimura, H., Young, J., Meltzer, S.J. Nat. Genet. (1996) [Pubmed]
  8. The insulin-like growth factor type-2 receptor gene is imprinted in the mouse but not in humans. Kalscheuer, V.M., Mariman, E.C., Schepens, M.T., Rehder, H., Ropers, H.H. Nat. Genet. (1993) [Pubmed]
  9. Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Haig, D., Graham, C. Cell (1991) [Pubmed]
  10. Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Ong, K., Kratzsch, J., Kiess, W., Costello, M., Scott, C., Dunger, D. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  11. Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis? Cianfarani, S., Geremia, C., Scott, C.D., Germani, D. Pediatr. Res. (2002) [Pubmed]
  12. Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells. Chen, Z., Ge, Y., Landman, N., Kang, J.X. BMC Cancer (2002) [Pubmed]
  13. Estradiol down-regulates the mannose-6-phosphate/insulin-like growth factor-II receptor gene and induces cathepsin-D in breast cancer cells: a receptor saturation mechanism to increase the secretion of lysosomal proenzymes. Mathieu, M., Vignon, F., Capony, F., Rochefort, H. Mol. Endocrinol. (1991) [Pubmed]
  14. Structure of a functional IGF2R fragment determined from the anomalous scattering of sulfur. Brown, J., Esnouf, R.M., Jones, M.A., Linnell, J., Harlos, K., Hassan, A.B., Jones, E.Y. EMBO J. (2002) [Pubmed]
  15. The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation. Sacher, M., Di Bacco, A., Lunin, V.V., Ye, Z., Wagner, J., Gill, G., Cygler, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  16. Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Sandovici, I., Leppert, M., Hawk, P.R., Suarez, A., Linares, Y., Sapienza, C. Hum. Mol. Genet. (2003) [Pubmed]
  17. Domain interactions of the mannose 6-phosphate/insulin-like growth factor II receptor. Kreiling, J.L., Byrd, J.C., MacDonald, R.G. J. Biol. Chem. (2005) [Pubmed]
  18. The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor. Di Bacco, A., Gill, G. Oncogene (2003) [Pubmed]
  19. 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]
  20. The IGF2 receptor is a USF2-specific target in nontumorigenic mammary epithelial cells but not in breast cancer cells. Szentirmay, M.N., Yang, H.X., Pawar, S.A., Vinson, C., Sawadogo, M. J. Biol. Chem. (2003) [Pubmed]
  21. Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population. Payton, A., Holland, F., Diggle, P., Rabbitt, P., Horan, M., Davidson, Y., Gibbons, L., Worthington, J., Ollier, W.E., Pendleton, N. Mol. Psychiatry (2003) [Pubmed]
  22. Opposing roles for the insulin-like growth factor (IGF)-II and mannose 6-phosphate (Man-6-P) binding activities of the IGF-II/Man-6-P receptor in the growth of prostate cancer cells. Schaffer, B.S., Lin, M.F., Byrd, J.C., Park, J.H., MacDonald, R.G. Endocrinology (2003) [Pubmed]
  23. Contribution of residues A54 and L55 of the human insulin-like growth factor-II (IGF-II) A domain to Type 2 IGF receptor binding specificity. Forbe, B.E., McNeil, K.A., Scott, C.D., Surinya, K.H., Cosgrove, L.J., Wallace, J.C. Growth Factors (2001) [Pubmed]
  24. Type-2 IGF receptor: a multi-ligand binding protein. Braulke, T. Horm. Metab. Res. (1999) [Pubmed]
  25. Inhibition of insulin like growth factor II autocrine growth of Wilms' tumor by suramin in vitro and in vivo. Vincent, T.S., Hazen-Martin, D.J., Garvin, A.J. Cancer Lett. (1996) [Pubmed]
  26. M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1. Godár, S., Horejsi, V., Weidle, U.H., Binder, B.R., Hansmann, C., Stockinger, H. Eur. J. Immunol. (1999) [Pubmed]
  27. Binding of urokinase-type plasminogen activator receptor (uPAR) to the mannose 6-phosphate/insulin-like growth factor II receptor: contrasting interactions of full-length and soluble forms of uPAR. Kreiling, J.L., Byrd, J.C., Deisz, R.J., Mizukami, I.F., Todd, R.F., MacDonald, R.G. J. Biol. Chem. (2003) [Pubmed]
  28. Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Zhu, Y., Doray, B., Poussu, A., Lehto, V.P., Kornfeld, S. Science (2001) [Pubmed]
  29. A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. Scott, G.K., Fei, H., Thomas, L., Medigeshi, G.R., Thomas, G. EMBO J. (2006) [Pubmed]
  30. Rat C6 glial cells synthesize insulin-like growth factor I (IGF-I) and express IGF-I receptors and IGF-II/mannose 6-phosphate receptors. Kiess, W., Lee, L., Graham, D.E., Greenstein, L., Tseng, L.Y., Rechler, M.M., Nissley, S.P. Endocrinology (1989) [Pubmed]
  31. The insulin-like growth factor-II receptor gene is associated with type 1 diabetes: evidence of a maternal effect. McCann, J.A., Xu, Y.Q., Frechette, R., Guazzarotti, L., Polychronakos, C. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  32. Expression of the insulin-like growth factors and their receptors in term placentas: a comparison between normal and IUGR births. Abu-Amero, S.N., Ali, Z., Bennett, P., Vaughan, J.I., Moore, G.E. Mol. Reprod. Dev. (1998) [Pubmed]
  33. Genetic changes and expression of the mannose 6-phosphate/insulin-like growth factor II receptor gene in human hepatitis B virus-associated hepatocellular carcinoma. Yang, E.B., Qin, L.L., Zhao, Y.N., Zhang, K., Chow, P. Int. J. Mol. Med. (2003) [Pubmed]
  34. Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height. Petry, C.J., Ong, K.K., Wingate, D.L., Brown, J., Scott, C.D., Jones, E.Y., Pembrey, M.E., Dunger, D.B. Growth Horm. IGF Res. (2005) [Pubmed]
  35. Differential expression of the mannose 6-phosphate/ insulin-like growth factor-II receptor in human breast cancer cell lines of different invasive potential. Xie, S., Kang, J.X. Med. Sci. Monit. (2002) [Pubmed]
  36. Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer. Hu, C.K., McCall, S., Madden, J., Huang, H., Clough, R., Jirtle, R.L., Anscher, M.S. Prostate Cancer Prostatic Dis. (2006) [Pubmed]
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