title: Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.
abstract: BACKGROUND
  Insulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2.
  
  
  RESULTS
  In this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation.
  
  
  CONCLUSIONS
  This study provides novel insight into the mechanism of receptor binding and activation by IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer.
authors.affiliation: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, Australia.
authors.forename: Clair L
authors.initials: CL
authors.lastname: Alvino
authors.forename: Shee Chee
authors.initials: SC
authors.lastname: Ong
authors.forename: Kerrie A
authors.initials: KA
authors.lastname: McNeil
authors.forename: Carlie
authors.initials: C
authors.lastname: Delaine
authors.forename: Grant W
authors.initials: GW
authors.lastname: Booker
authors.forename: John C
authors.initials: JC
authors.lastname: Wallace
authors.forename: Briony E
authors.initials: BE
authors.lastname: Forbes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D004789:Enzyme Activation; D057075:Enzyme Assays; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000737:chemistry; D007335:Insulin-Like Growth Factor II / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000096:biosynthesis / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000378:metabolism*; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D050505:Mutant Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt