Abstract
Up to 90% of circulating insulin-like growth factors (IGF-I and IGF-II) are carried in heterotrimeric complexes with a binding protein (IGFBP) and a liver-derived glycoprotein known as the acid-labile subunit. IGFBP-3 is considered unique among the six well characterized IGFBPs in its ability to complex with the acid-labile subunit. However, a basic carboxyl-terminal domain of IGFBP-3, known to be involved in its interaction with the acid-labile subunit, is shared by IGFBP-5, suggesting the possibility of ternary complexes containing IGFBP-5. We now demonstrate using three independent methods that human IGFBP-5, when occupied by IGF-I or IGF-II, forms ternary complexes of approximately 130 kDa with the acid-labile subunit. IGFBP-3 competes with approximately twice the potency of IGFBP-5 for the formation of such complexes. No other IGFBP complexes with the acid-labile subunit itself or competes with IGFBP-5 for complex formation. As observed for IGFBP-3, ternary complexes containing IGFBP-5 form preferentially in the presence of IGF-I, even though IGFBP-5 has a preferential affinity for IGF-II over IGF-I. By size fractionation chromatography, serum IGFBP-5 co-elutes predominantly with ternary complexes. The demonstration of IGFBP-5-containing ternary complexes indicates an unrecognized form of IGF transport in the circulation and an additional mechanism for regulating IGF bioavailability.
Highlights
The insulin-like growth factors (IGFs),1 which have both anabolic and mitogenic activity, play a critical role in cell and tissue growth regulation throughout life and in the maintenance of glucose homeostasis [1,2,3]
Complexes of IGF-binding protein (IGFBP)-5 with acid-labile subunit (ALS) and IGF-I or IGF-II have been demonstrated using three independent methods: gel per-. Peptides corresponding to this basic domain have been shown to inhibit IGFBP-3 and IGFBP-5 binding to endothelial cells [37], and mutation of IGFBP-3 residues 228 –232 (KGRKR) to the corresponding residues of IGFBP-1 (MDGEA) prevents IGFBP-3 cell association [16]
The unique sharing of this basic structural domain involved in ALS binding, between IGFBP-3 and IGFBP-5, which are suggested to have evolved from a common gene [38], may account for their shared ability to form ALS complexes and for other shared functions such as cell surface and matrix binding [37, 39] of these two proteins
Summary
The insulin-like growth factors (IGFs),1 which have both anabolic and mitogenic activity, play a critical role in cell and tissue growth regulation throughout life and in the maintenance of glucose homeostasis [1,2,3]. We report that IGFBP-5, like IGFBP-3, binds to ALS in the presence of IGFs and is detectable in high molecular weight form in human serum.
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