title: Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes.
abstract: The cation-independent mannose-6-phosphate/insulin-like growth factor-II receptor (IGF2R) is a membrane-bound glycoprotein consisting of 15 homologous extracellular repeat domains. The major function of this receptor is trafficking of lysosomal enzymes from the trans-Golgi network to the endosomes and their subsequent transfer to lysosomes. The IGF2R also plays a major role in binding and regulating the circulating and tissue levels of IGF-II. As this ligand is important for cell growth, survival, and migration, the maintenance of correct IGF-II levels influences its actions in normal growth and development. Deregulation of IGF2R expression has therefore been associated with growth related disease and cancer. This review highlights recent advances in understanding the IGF2R structure and mechanism of interaction with its ligands, in particular IGF-II. Recent mutagenesis studies combined with the crystal structure of domains 11-14 in complex with IGF-II have mapped the sites of interaction and explain how the IGF2R specificity for IGF-II is achieved. The role of domain 13 in high-affinity IGF-II binding is also revealed. Characterization of ligand:IGF2R interactions is vital for the understanding of the mechanism of IGF2R actions and will allow the development of specific cancer therapies in the future.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.forename: E Y
authors.initials: EY
authors.lastname: Jones
authors.forename: B E
authors.initials: BE
authors.lastname: Forbes
mesh_terms: D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II