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dc.contributor.authorHeadey, Stephen Jen
dc.contributor.authorLeeding, Kerri Sen
dc.contributor.authorNorton, Raymond Sen
dc.contributor.authorBach, Leon Aen
dc.date.accessioned2015-05-15T23:04:53Z
dc.date.available2015-05-15T23:04:53Z
dc.date.issued2004-10-01en
dc.identifier.citationJournal of Molecular Endocrinology; 33(2): 377-86en
dc.identifier.govdoc15525596en
dc.identifier.otherPUBMEDen
dc.identifier.urihttp://ahro.austin.org.au/austinjspui/handle/1/9826en
dc.description.abstractInsulin-like growth factors IGF-I and IGF -II are important mediators of growth. A family of six high affinity IGF binding proteins (IGFBPs) modulate IGF action. IGFBPs have three domains, of which the N- and C-domains are involved in high affinity IGF binding. IGFBP-6 is unique in its 20-100-fold IGF-II binding specificity over IGF-I. The aim of this study was to determine the contributions of the N- and C-domains of IGFBP-6 to its IGF binding properties. We confirmed that differential dissociation kinetics are responsible for the IGF-II binding preference of IGFBP-6. The N-domain has rapid association kinetics, similar to full-length IGFBP-6, but both IGF-I and -II dissociate rapidly from this domain, thereby reducing its binding affinity for IGF-II approximately 50-fold. However, the N-domain binds IGF-I and -II with similar affinities and it has a similar IGF-I binding affinity to full-length IGFBP-6. This suggests that the C-domain confers the IGF-II binding preference of IGFBP-6; indeed, IGF-I bound inconsistently with very low affinity to the C-domain. Coincubation studies showed that isolated N- and C-domains of IGFBP-6 do not strongly cooperate to enhance IGF binding. The results of the binding studies are supported by the effects of the IGFBP-6 domains on IGF-induced colon cancer cell proliferation; the N-domain inhibited IGF-II induced proliferation with approximately 20-fold lower potency than IGFBP-6 and it was equipotent in inhibiting IGF-I- and IGF-II-induced proliferation. Coincubation of C-domain had no additional effect on N-domain-induced inhibition of proliferation. In conclusion, both the N- and C-domains of IGFBP-6 are involved in IGF binding, the C-domain is responsible for the IGF-II binding preference of IGFBP-6 and intact IGFBP-6 is necessary for high affinity IGF binding.en
dc.language.isoenen
dc.subject.otherBiosensing Techniquesen
dc.subject.otherCell Proliferation.drug effectsen
dc.subject.otherColonic Neoplasms.drug therapy.metabolism.pathologyen
dc.subject.otherHumansen
dc.subject.otherInsulin-Like Growth Factor Binding Protein 6.genetics.metabolism.pharmacologyen
dc.subject.otherInsulin-Like Growth Factor I.genetics.metabolismen
dc.subject.otherInsulin-Like Growth Factor II.genetics.metabolismen
dc.subject.otherKineticsen
dc.subject.otherPeptide Fragments.genetics.metabolism.pharmacologyen
dc.subject.otherProtein Structure, Tertiaryen
dc.subject.otherTumor Cells, Cultureden
dc.titleContributions of the N- and C-terminal domains of IGF binding protein-6 to IGF binding.en
dc.typeJournal Articleen
dc.identifier.journaltitleJournal of molecular endocrinologyen
dc.identifier.affiliationUniversity of Melbourne, Department of Medicine, Austin Hospital, Heidelberg 3084, Australiaen
dc.identifier.doi10.1677/jme.1.01547en
dc.description.pages377-86en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/15525596en
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