Insulin-like growth factor 2 receptor

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IGF2R
Protein IGF2R PDB 1e6f.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIGF2R, CD222, CIMPR, M6P-R, MPR1, MPRI, M6P/MPR 300, CI-M6PR, MPR300, insulin like growth factor 2 receptor
External IDsOMIM: 147280 MGI: 96435 HomoloGene: 676 GeneCards: IGF2R
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000876

NM_010515

RefSeq (protein)

NP_000867

NP_034645

Location (UCSC)Chr 6: 159.97 – 160.11 MbChr 17: 12.9 – 12.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] 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.[6]

Structure

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.[7] 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.

Function

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.[7] The IGF2Rs (bound to their cargo) are recognized by the GGA family of clathrin adaptor proteins and accumulate in forming clathrin-coated vesicles.[8] 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.

Interactions

Insulin-like growth factor 2 receptor has been shown to interact with M6PRBP1.[9][10]

Evolution

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.[11]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197081 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023830 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. doi:10.1016/S0021-9258(18)69243-9. PMID 2963003.
  6. ^ 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. doi:10.1016/0888-7543(88)90083-3. PMID 2852162.
  7. ^ 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. doi:10.1038/nrm1050. PMID 12612639. S2CID 16991464.
  8. ^ 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. doi:10.1078/0171-9335-00374. PMID 15511083.
  9. ^ Díaz E, Pfeffer SR (May 1998). "TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking". Cell. 93 (3): 433–43. doi:10.1016/S0092-8674(00)81171-X. PMID 9590177. S2CID 17161071.
  10. ^ 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. Bibcode:2000PNAS...97.9047O. doi:10.1073/pnas.160251397. PMC 16819. PMID 10908666.
  11. ^ 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. Bibcode:2012Sci...338.1209W. doi:10.1126/science.1228633. PMC 4658703. PMID 23197533.

Further reading

External links