IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Abstract

Traditionally, binding proteins are known to regulate the activity of ligands by prolonging their half-life, and insulin-like growth factor (IGF)-binding proteins (IGFBPs) are no exception to this. The IGFBP family contains six high-affinity members with variable functions and mechanisms of actions. In addition to functioning as simple carrier proteins, IGFBPs in serum function to regulate the endocrine actions of IGFs by regulating the amount of IGF available to bind to signaling IGF-I receptors, whereas locally produced IGFBPs act as autocrine/paracrine regulators of IGF action. Furthermore, recent in vitro and in vivo findings that IGFBPs function independently of the IGFs as growth modulators are particularly exciting. Regarding the role of IGFBPs as ligand-independent growth modulators, our recent data that IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs provide evidence that IGFBP-5 itself is a growth factor that can act independently of IGFs to regulate bone formation. In terms of the mechanism by which certain IGFBPs mediate their effects in a ligand-independent manner, the binding of IGFBP to its putative receptor on the cell membrane may stimulate the signaling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBPs may also exert IGF-independent effects by transcriptional activation of genes by IGFBPs transported into the nucleus via their nuclear localization signal. In conclusion, IGFBPs are unusually pleotrophic molecules with functions ranging from the traditional role of prolonging the half-life of the IGFs to functioning as growth factors independent of the IGFs. In this regard, it was surprising to find that the human genome contains only about 35 000 genes. One mechanism to account for such complexity with a relatively small number of genes is strikingly illustrated by the multifunctional IGFBP class of proteins.

Cell cycle regulation and hepatocarcinogenesis

“…IGFBP proteins are also able to exert IGF independent effects through modulation of integrin signaling pathways and in some instances by transcriptional activation of target genes. 81,83 The potential for IGFBP-1 to directly regulate growth associated genes has not yet been demonstrated.…”

The GH–IGF-I axis and breast cancer

“…The smaller complexes are able to pass the vascular endothelial barrier and therefore may be important modulators of IGF-1 activity at the cellular level 21 . IGFBPs especially IGFBP-3 have independent effects on cell growth, for example IGFBP-3 has proapoptotic activities both dependent on and independent of p53 22 . IGFBP-3 may indirectly influence tumourigenesis by binding IGF-1 and thereby inhibiting the mitogenic effects of IGF-1.…”

Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease

“…In the aggregate to IGF-binding, a number of IGF-independent functions have been described for IGFBPs, many of which occur through interaction with extracellular matrix (ECM) components (Miyakoshi et al, 2001;Bach et al, 2005). Alternatively, IGFBPs can translocate to the nucleus with the help of importin b and act as transcriptional regulators (Mohan and Baylink, 2002;Burger et al, 2005). Such IGF-independent functions have implications not only in cell growth inhibition, the promotion of apoptosis and the modulation of cell adhesion and migration, but also in cancer.…”