Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/70705
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Type: Journal article
Title: Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II
Author: Alvino, C.
Ong, S.
McNeil, K.
Delaine, C.
Booker, G.
Wallace, J.
Forbes, B.
Citation: PLoS One, 2011; 6(11):1-9
Publisher: Public Library of Science
Issue Date: 2011
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
Clair L. Alvino, Shee Chee Ong, Kerrie A. McNeil, Carlie Delaine, Grant W. Booker, John C. Wallace and Briony E. Forbes
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. Methodology/Principal Findings: 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/Significance: This study provides novel insight into the mechanism of receptor binding and activation by IGFII,which may be important for the future development of inhibitors of its action for the treatment of cancer.
Keywords: Animals; Mice; Receptor, IGF Type 1; Receptor, Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Sequence Alignment; Signal Transduction; Binding, Competitive; Enzyme Activation; Amino Acid Sequence; Protein Binding; Phosphorylation; Molecular Sequence Data; Mutant Proteins; Proto-Oncogene Proteins c-akt; Enzyme Assays
Description: Extent: 9p.
Rights: Copyright: 2011 Alvino et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
RMID: 0020115378
DOI: 10.1371/journal.pone.0027488
Appears in Collections:Molecular and Biomedical Science publications

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