Effect of IGFBP-3 on IGF- and IGF-analogue-induced insulin-like growth factor-1 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 affin iy of the IGFs for the IGFIR. It has been hypothesized that IGFBP-3 inhibit s IGF binding to the IGFIR via a mechanism independent of its ability to se quester IGFs. In the present study, we examined the effects of IGFBP-3 and its proteolytic fragments on the initial events of the IGFIR signalling pat hway. IGFBP-3 inhibited IGF-I-, IGF-II-, Des(1-3)IGF-I- and Long(R3)IGF-I-i nduced IGFIR phosphorylation in a dose-dependent manner at similar concentr ation range but not QAYL-induced IGFIR-P The ((1-97))IGFBP-3 fragment was a ble to inhibit only IGF-I-induced IGFIR-P. The ((1-97))IGFBP-3 fragment but not intact IGFBP-3 inhibited insulininduced IGFIR-P. Monolayer cross-linki ng with [I-125]IGFBP-3 indicated that there is no direct interaction of IGF BP-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 seque ster IGF and the IGF analogues in the extracellular milieu and not the resu lt of any interaction of IGFBP-3 with the IGFIR or a mechanism independent of its ability to bind IGFs. (C) 2001 Harcourt Publishers Ltd.