Studies on the Mechanisms by Which Insulin-like Growth Factor (IGF) Binding Protein-4 (IGFBP-4) and IGFBP-5 Modulate IGF Actions in Bone Cells

Abstract

The growth potentiating effects of the insulin-like growth factor (IGF)-I and IGF-II are modulated by a family of six insulin-like growth factor binding proteins (IGFBPs). Despite the similarity in amino acid sequences of the IGFBPs, their effects on the growth of bone cells differ. Studies on the molecular mechanisms for IGFBP-4 actions revealed that coincubation of bone cells with IGFBP-4 and 125I-IGF-I or 125I-IGF-II decreased the binding of both of these ligands in a dose-dependent manner. In addition, IGFBP-4 decreased the binding of IGF-I tracer to purified type I IGF receptor. These data in conjunction with data showing that IGFBP-4 had no effect on cell proliferation induced by analogs of IGF-I or IGF-II, which exhibited > 100-fold reduced affinity for binding to IGFBP-4 suggest that IGFBP-4 may inhibit IGF action by preventing the binding of ligand to its membrane receptor. In contrast to IGFBP-4, IGFBP-5 treatment increased the binding of IGF tracer to bone cells but did not increase the binding of 125I-IGF-I to type I IGF receptor. Studies on the mechanism by which IGFBP-5 increased the binding of 125I-IGF tracer to bone cells suggest that IGFBP-5 could facilitate IGF binding by a mechanism in which IGFBP-5 has cell surface binding sites independent of IGF receptors. These data in conjunction with the findings that IGFBP-5 potentiated cell proliferation even in the presence of those same IGF analogs that exhibited > 200-fold reduced affinity for binding to IGFBP-5, suggest that IGFBP-5 may in part stimulate bone cell proliferation by an IGF-independent mechanism involving IGFBP-5-specific cell surface binding sites.

Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity

“…However, our ChIP assay results suggest that N-terminally tagged full-length IGFBP-5 is associated with the histone-DNA complex. In addition, two Gal4DBD constructs encoding the natural 21-to 22-kDa IGFBP-5 proteolytic fragments had no transactivation activity, 3 suggesting that proteolytic cleavage at Lys 138 /Lys 139 and Ser 143 /Leu 144 may not play any major role in unmasking the transactivation activity of IGFBP-5.…”

“…Besides binding to IGF and modulating its actions, IGFBP-5 has been reported to regulate cell proliferation (2,3), migration (4 -6), and apoptosis/survival (7-11) independent of IGF. Although the ligand-dependent actions of IGFBP-5 are attributed to its interactions with the IGF ligand and other proteins (1), the mechanistic basis of the ligand-independent actions of IGFBP- 5 is not yet understood.…”

Nuclear Import of Insulin-like Growth Factor-binding Protein-3 and -5 Is Mediated by the Importin β Subunit

“…These effects on cell growth may be mediated by IGFBP-3 in an IGF-independent manner. There are fewer reports of IGF-independent effects of IGFBP-5; these include its ability to stimulate bone cell growth in the absence of increased IGF-I binding to its receptor (8). The mechanism(s) for the IGFindependent effects of IGFBP-3 and IGFBP-5 are currently unknown but may involve a direct nuclear action.…”

Interactions of High Affinity Insulin-like Growth Factor-binding Proteins with the Type V Transforming Growth Factor-β Receptor in Mink Lung Epithelial Cells

“…They coordinate and regulate the biological activities of IGF-I and IGF-II by serving as transporter proteins or carriers and by scavenging IGFs from IGF receptors (1)(2)(3). High affinity IGFBPs have also been shown to induce cellular responses in an IGF-independent manner (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). These IGF-independent actions of high affinity IGFBPs are believed to be mediated by specific cell-surface receptors or membrane proteins (6, 16 -18).…”