In biochemistry and cell biology, the insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR), is a multifunctional protein receptor that binds insulin-like growth factor 2 (IGF2) at the cell surface and mannose-6-phosphate (M6P)-tagged proteins in the trans-Golgi network.
The structure of the IGF2R is a type I transmembrane protein (that is, it has a single transmembrane domain with its C-terminus on the cytoplasmic side of lipid membranes) with a large extracellular/lumenal domain and a relatively short cytoplasmic tail (Ghosh, Dahms & Kornfeld 2003). The extracellular domain consists a small region homologous to the collagen-binding domain of fibronectin and of fifteen repeats of approximately 147 amino acid residues. Each of these repeats is homologous to the 157-residue extracytoplasmic domain of the mannose 6-phosphate receptor. Binding to IGF2 is mediated through one of the repeats, while two different repeats are responsible for binding to mannose-6-phosphate. The IGF2R is approximately 300 kDa in size it appears to exist and function as a dimer.
IGF2R functions to clear IGF2 from the cell surface to attenuate signalling, and to transport lysosomal acid hydrolase precursors from the Golgi apparatus to the lysosome. After binding IGF2 at the cell surface, IGF2Rs accumulate in forming clathrin-coated vesicles and are internalized. In the lumen of the trans-Golgi network, the IGF2R binds M6P-tagged cargo (Ghosh, Dahms & Kornfeld 2003). The IGF2Rs (bound to their cargo) are recognized by the GGA family of clathrin adaptor proteins and accumulate in forming clathrin-coated vesicles (Ghosh & Kornfeld 2004). IGF2Rs from both the cell surface and the Golgi are trafficked to the early endosome where, in the relatively low pH environment of the endosome, the IGF2Rs release their cargo. The IGF2Rs are recycled back to the Golgi, again by way of interaction with GGAs and vesicles. The cargo proteins are then trafficked to the lysosome via the late endosome independently of the IGF2Rs.
Ghosh, Pradipta; Dahms, Nancy H. & Kornfeld, Stuart (2003), " ", Nature Reviews Molecular and Cell Biology4: 203-121, PMID 12612639
Ghosh, Pradipta & Kornfeld, Stuart (2004), " ", European Journal of Cell Biology83: 257-262, PMID 15511083
O'Dell SD, Day IN (1998). "Insulin-like growth factor II (IGF-II).". Int. J. Biochem. Cell Biol.30 (7): 767-71. PMID 9722981.
Hawkes C, Kar S (2004). "The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system.". Brain Res. Brain Res. Rev.44 (2-3): 117-40. doi:10.1016/j.brainresrev.2003.11.002. PMID 15003389.
Scott CD, Firth SM (2005). "The role of the M6P/IGF-II receptor in cancer: tumor suppression or garbage disposal?". Horm. Metab. Res.36 (5): 261-71. doi:10.1055/s-2004-814477. PMID 15156403.
Antoniades HN, Galanopoulos T, Neville-Golden J, Maxwell M (1992). "Expression of insulin-like growth factors I and II and their receptor mRNAs in primary human astrocytomas and meningiomas; in vivo studies using in situ hybridization and immunocytochemistry.". Int. J. Cancer50 (2): 215-22. PMID 1370435.
Zhou J, Bondy C (1992). "Insulin-like growth factor-II and its binding proteins in placental development.". Endocrinology131 (3): 1230-40. PMID 1380437.
Morgan DO, Edman JC, Standring DN, et al. (1987). "Insulin-like growth factor II receptor as a multifunctional binding protein.". Nature329 (6137): 301-7. doi:10.1038/329301a0. PMID 2957598.
Oshima A, Nolan CM, Kyle JW, et al. (1988). "The human cation-independent mannose 6-phosphate receptor. Cloning and sequence of the full-length cDNA and expression of functional receptor in COS cells.". J. Biol. Chem.263 (5): 2553-62. PMID 2963003.
De Souza AT, Hankins GR, Washington MK, et al. (1996). "M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity.". Nat. Genet.11 (4): 447-9. doi:10.1038/ng1295-447. PMID 7493029.
Ilvesmäki V, Blum WF, Voutilainen R (1994). "Insulin-like growth factor binding proteins in the human adrenal gland.". Mol. Cell. Endocrinol.97 (1-2): 71-9. PMID 7511544.
De Souza AT, Hankins GR, Washington MK, et al. (1995). "Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors.". Oncogene10 (9): 1725-9. PMID 7753549.
Schmidt B, Kiecke-Siemsen C, Waheed A, et al. (1995). "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 (25): 14975-82. PMID 7797478.
Rao PH, Murty VV, Gaidano G, et al. (1994). "Subregional mapping of 8 single copy loci to chromosome 6 by fluorescence in situ hybridization.". Cytogenet. Cell Genet.66 (4): 272-3. PMID 8162705.
Ishiwata T, Bergmann U, Kornmann M, et al. (1997). "Altered expression of insulin-like growth factor II receptor in human pancreatic cancer.". Pancreas15 (4): 367-73. PMID 9361090.
Tikkanen R, Peltola M, Oinonen C, et al. (1998). "Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase.". EMBO J.16 (22): 6684-93. doi:10.1093/emboj/16.22.6684. PMID 9362483.
Nykjaer A, Christensen EI, Vorum H, et al. (1998). "Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction.". J. Cell Biol.141 (3): 815-28. PMID 9566979.
Díaz E, Pfeffer SR (1998). "TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking.". Cell93 (3): 433-43. PMID 9590177.
Wan L, Molloy SS, Thomas L, et al. (1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization.". Cell94 (2): 205-16. PMID 9695949.
Killian JK, Jirtle RL (1999). "Genomic structure of the human M6P/IGF2 receptor.". Mamm. Genome10 (1): 74-7. PMID 9892739.
Kumar S, Hand AT, Connor JR, et al. (1999). "Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functions.". J. Biol. Chem.274 (24): 17123-31. PMID 10358067.