Effect of IGFBP-3 on IGF- and IGF-analogue-induced insulin-like growth factor-I receptor (IGFIR) signalling.
Insulin-like growth factor binding protein-3 (IGFBP-3) binds IGF-I and IGF-II with high affinity, at least an order of magnitude higher than the affiniy of the IGFs for the IGFIR. It has been hypothesized that IGFBP-3 inhibits IGF binding to the IGFIR via a mechanism independent of its ability to sequester IGFs. In the present study, we examined the effects of IGFBP-3 and its proteolytic fragments on the initial events of the IGFIR signalling pathway. IGFBP-3 inhibited IGF-I-, IGF-II-, Des(1-3)IGF-I- and Long(R3)IGF-I-induced IGFIR phosphorylation in a dose-dependent manner at similar concentration range but not QAYL-induced IGFIR-P. The((1-97))IGFBP-3 fragment was able to inhibit only IGF-I-induced IGFIR-P. The((1-97))IGFBP-3 fragment but not intact IGFBP-3 inhibited insulin-induced IGFIR-P. Monolayer cross-linking with [(125)I]IGFBP-3 indicated that there is no direct interaction of IGFBP-3 with the IGFIR. This study demonstrates that the effect on the initial step of IGFIR signalling by IGFBP-3 is largely due to its ability to sequester IGF and the IGF analogues in the extracellular milieu and not the result of any interaction of IGFBP-3 with the IGFIR or a mechanism independent of its ability to bind IGFs.
Devi
G R
GR
Department of Pediatrics, School of Medicine, Oregon Health Sciences University, Portland, OR 97201-3042, USA. grdevi@avibio.com
Graham
D L
DL
Oh
Y
Y
Rosenfeld
R G
RG
D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007328:Insulin / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction
D003432:Cross-Linking Reagents; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1