Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.

dc.contributor.author Alvino, Clair L
dc.contributor.author Ong, Sheechee
dc.contributor.author McNeil, Kerrie A
dc.contributor.author Delaine, Carlie A
dc.contributor.author Booker, Grant W
dc.contributor.author Wallace, John C
dc.contributor.author Forbes, Briony E
dc.date.accessioned 2017-03-09T03:21:22Z
dc.date.available 2017-03-09T03:21:22Z
dc.date.issued 2011-11-28
dc.description.abstract 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 IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer. en
dc.identifier.citation Alvino CL, Ong SC, McNeil KA, Delaine C, Booker GW, Wallace JC, Forbes BE. Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II. PLoS One. 2011;6(11):e27488. doi: 10.1371/journal.pone.0027488. en
dc.identifier.doi https://doi.org/10.1371/journal.pone.0027488 en
dc.identifier.uri http://hdl.handle.net/2328/36957
dc.language.iso en
dc.oaire.license.condition.license CC-BY
dc.publisher PLOS en
dc.title Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II. en
dc.type Article en
local.contributor.authorOrcidLookup Forbes, Briony E: https://orcid.org/0000-0003-4360-9927 en_US
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