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). .
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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|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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