Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer
| Autor: | Lesley A. Pearce, Xiaowen Xiao, Sameer A. Greenall, Nicola A. Bartone, Lindsay G. Sparrow, Leah J. Cosgrove, John D. Bentley, Robert C. Baxter, Timothy E. Adams, Judith A. Scoble |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
Glycosylation medicine.medical_treatment Biochemistry Mass Spectrometry Receptor tyrosine kinase Insulin-like growth factor-binding protein Mice Insulin-Like Growth Factor II Neoplasms medicine Animals Humans Protein Isoforms Insulin-Like Growth Factor I Receptor Molecular Biology Cell Proliferation biology Growth factor Receptor Protein-Tyrosine Kinases Molecular Bases of Disease Cell Biology Fibroblasts Protein Structure Tertiary Gene Expression Regulation Neoplastic Insulin-Like Growth Factor Binding Proteins Insulin receptor HEK293 Cells Ectodomain biology.protein Signal transduction Protein Binding Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 288:59-68 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.432013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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