title: Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer.
abstract: Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.
authors.affiliation: Division of Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Parkville, Victoria 3052, Australia.
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Greenall
authors.forename: John D
authors.initials: JD
authors.lastname: Bentley
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Pearce
authors.forename: Judith A
authors.initials: JA
authors.lastname: Scoble
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Sparrow
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Bartone
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Xiao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Cosgrove
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Adams
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry; D007334:Insulin-Like Growth Factor I / Q000737:chemistry; D007335:Insulin-Like Growth Factor II / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D020794:Receptor Protein-Tyrosine Kinases