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Insulin-like growth factor 2 receptor

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Title: Insulin-like growth factor 2 receptor  
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Subject: Insulin-like growth factor 2, Somatomedin receptor, Clusters of differentiation, Leptin receptor, Kinase insert domain receptor
Collection: Clusters of Differentiation, Receptors
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Insulin-like growth factor 2 receptor

Insulin-like growth factor 2 receptor
PDB rendering based on 1e6f.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; CD222; CIMPR; M6P-R; MPR1; MPRI
External IDs ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the IGF2R gene.[1][2] IGF2R 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.[2]


  • Structure 1
  • Function 2
  • Interactions 3
  • Evolution 4
  • See also 5
  • References 6
  • Further reading 7
  • External links 8


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.[3] The extracellular domain consists of 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.[3] The IGF2Rs (bound to their cargo) are recognized by the GGA family of clathrin adaptor proteins and accumulate in forming clathrin-coated vesicles.[4] 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 by the retromer complex, 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.


Insulin-like growth factor 2 receptor has been shown to interact with M6PRBP1.[5][6]


The insulin-like growth factor 2 receptor function evolved from the cation-independent mannose 6-phosphate receptor and is first seen in Monotremes. The IGF-2 binding site was likely acquired fortuitously with the generation of an exonic splice site enhancer cluster in exon 34, presumably necessitated by several kilobases of repeat element insertions in the preceding intron. A six-fold affinity maturation then followed during therian evolution, coincident with the onset of imprinting and consistent with the theory of parental conflict. [7]

See also


  1. ^ Oshima A, Nolan CM, Kyle JW, Grubb JH, Sly WS (February 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.  
  2. ^ a b Laureys G, Barton DE, Ullrich A, Francke U (October 1988). "Chromosomal mapping of the gene for the type II insulin-like growth factor receptor/cation-independent mannose 6-phosphate receptor in man and mouse". Genomics 3 (3): 224–9.  
  3. ^ a b Ghosh P, Dahms NM, Kornfeld S (March 2003). "Mannose 6-phosphate receptors: new twists in the tale". Nat. Rev. Mol. Cell Biol. 4 (3): 202–12.  
  4. ^ Ghosh P, Kornfeld S (July 2004). "The GGA proteins: key players in protein sorting at the trans-Golgi network". Eur. J. Cell Biol. 83 (6): 257–62.  
  5. ^ Díaz E, Pfeffer SR (May 1998). "TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking". Cell 93 (3): 433–43.  
  6. ^ Orsel JG, Sincock PM, Krise JP, Pfeffer SR (August 2000). "Recognition of the 300-kDa mannose 6-phosphate receptor cytoplasmic domain by 47-kDa tail-interacting protein". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9047–51.  
  7. ^ Williams C, Hoppe HJ, Rezgui D, Strickland M, Forbes BE, Grutzner F, Frago S, Ellis RZ, Wattana-Amorn P, Prince SN, Zaccheo OJ, Nolan CM, Mungall AJ, Jones EY, Crump MP, Hassan AB (November 2012). "Exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution". Science 338 (6111): 1209–1213.  

Further reading

  • O'Dell SD, Day IN (1998). "Insulin-like growth factor II (IGF-II)". Int. J. Biochem. Cell Biol. 30 (7): 767–71.  
  • 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.  
  • 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.  
  • 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. Cancer 50 (2): 215–22.  
  • Zhou J, Bondy C (1992). "Insulin-like growth factor-II and its binding proteins in placental development". Endocrinology 131 (3): 1230–40.  
  • Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ (1987). "Insulin-like growth factor II receptor as a multifunctional binding protein". Nature 329 (6137): 301–7.  
  • Oshima A, Nolan CM, Kyle JW, Grubb JH, Sly WS (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.  
  • De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL (1996). "M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity". Nat. Genet. 11 (4): 447–9.  
  • 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.  
  • De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL (1995). "Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors". Oncogene 10 (9): 1725–9.  
  • Schmidt B, Kiecke-Siemsen C, Waheed A, Braulke T, von Figura K (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.  
  • Rao PH, Murty VV, Gaidano G, Hauptschein R, Dalla-Favera R, Chaganti RS (1994). "Subregional mapping of 8 single copy loci to chromosome 6 by fluorescence in situ hybridization". Cytogenet. Cell Genet. 66 (4): 272–3.  
  • Ishiwata T, Bergmann U, Kornmann M, Lopez M, Beger HG, Korc M (1997). "Altered expression of insulin-like growth factor II receptor in human pancreatic cancer". Pancreas 15 (4): 367–73.  
  • Tikkanen R, Peltola M, Oinonen C, Rouvinen J, Peltonen L (1998). "Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase". EMBO J. 16 (22): 6684–93.  
  • Nykjaer A, Christensen EI, Vorum H, Hager H, Petersen CM, Røigaard H, Min HY, Vilhardt F, Møller LB, Kornfeld S, Gliemann J (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.  
  • Díaz E, Pfeffer SR (1998). "TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking". Cell 93 (3): 433–43.  
  • Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell 94 (2): 205–16.  
  • Killian JK, Jirtle RL (1999). "Genomic structure of the human M6P/IGF2 receptor". Mamm. Genome 10 (1): 74–7.  
  • Kumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, Fisher SM, Nuttall ME, Lipshutz DB, Zou C, Hwang SM, Votta BJ, James IE, Rieman DJ, Gowen M, Lee JC (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.  

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