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Structural investigations into the relationships of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) with vitronectin (VN)

Kricker, Jennifer Ann (2005) Structural investigations into the relationships of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) with vitronectin (VN). PhD thesis, Queensland University of Technology.

Abstract

Previous studies demonstrated that IGF-II binds directly to vitronectin (VN) while IGF-I binds poorly. However, binding of VN to integrins has been demonstrated to be essential for a range of IGF-I-stimulated biological effects including IGF binding protein-5 (IGFBP-5) production, IGF type-1 receptor autophosphorylation and cell

migration. Thus, this study examined the hypothesis that a link between IGF-I and

VN must occur and may be mediated through IGFBPs. Studies using competitive

binding assays with VN and [125I]-labelled IGFs in the absence and presence of

IGFBPs revealed IGFBP-4, IGFBP-5 and non-glycoyslated IGFBP-3 significantly

enhance binding of IGF-I to VN, while IGFBP-2 and glycosylated IGFBP-3 had a

smaller effect. Furthermore, binding studies with analogues indicate that

glycosylation status of IGFBP-3 and the heparin-binding domains of IGFBP-3 and

IGFBP-5 are important in this interaction. The functional significance of IGFs

binding to VN on cell migration in MCF-7 breast carcinoma cells was examined and

cell migration was found to be enhanced when VN was pre-bound to IGF-I in the

presence of IGFBP-3, -4 and -5. The effect required IGF:IGFBP:VN complex

formation; this was demonstrated by use of a non-IGFBP-binding analogue, des(1-

3)IGF-I. Additionally, higher doses of IGFs in the presence of VN also could

stimulate cell migration. Together, these data indicated the importance of IGFBPs

in modulating IGF-I binding to VN and that this binding has functional

consequences in cells. Future directions for this work include investigations into the

mechanisms underlying formation of the trimeric complex and the associated

signalling pathways involved.

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ID Code: 16063
Item Type: QUT Thesis (PhD)
Supervisor: Upton, Zee& Herington, Adrian
Keywords: Insulin growth factors, IGF-I, vitronectin, VN, IGF-I, binding proteins, IGFBPs
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Past > Schools > School of Life Sciences
Department: Faculty of Science
Institution: Queensland University of Technology
Copyright Owner: Copyright Jennifer Ann Kricker
Deposited On: 03 Dec 2008 13:55
Last Modified: 29 Oct 2011 05:42

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