Review
What's new in the IGF-binding proteins?

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Abstract

Since their initial discovery over 25 years ago as IGF carrier proteins, the insulin-like growth factor binding protein (IGFBP) family has grown to six members, ranging in size from 216 to 289 amino acids. The assumption over the years has been that this family of proteins, having higher affinities for IGF-I and IGF-II than does the IGF-IR, serves to block access of these ligands to the receptor. Although the need for such regulatory proteins is consistent with the constitutive secretion of IGFs from many cell types, it is not surprising that additional functions have begun to be uncovered for these proteins. This review will examine new and old actions of the IGFBPs from a biochemical and cell biological perspective.

Section snippets

Historical introduction and overview

Over the last few years we have witnessed a renewed interest in the chemistry and biology of the IGFBPs. The new awareness of these proteins stems from numerous reports demonstrating that they exhibit a multitude of direct cellular actions that appear to be separate from their roles as IGF carrier proteins. A number of observations, which could not be explained on the basis of the paradigm of IGFBP action modulating IGF availability and function, led to the hypothesis that some of the IGFBPs

IGFBP structure: will the real IGF-binding domain please stand up?

The IGFBPs comprise a family of six soluble proteins ranging in length from 216 to 289 amino acids (Fig. 1). Based on their primary structures, each IGFBP may be divided into three distinct domains of approximately equal size. The NH2- and COOH-termini are highly conserved and contain 16–18 spatially conserved cysteine residues that form the various intra-domain disulfide bonds [1], [5]. The middle or linker domain is the least conserved region of the protein family, exhibiting <30% primary

Analysis of IGF-I:IGFBP interactions

Ligand blotting is a rapid, qualitative, and at least semi-quantitative technique for studying the IGFBPs [27]. This method additionally provides a means of examining “biologically relevant” IGFBPs, as misfolded, degraded or denatured proteins will not be detected. Few changes have been introduced into this method since its inception in 1986. A number of laboratories have applied the use of substituted biotinylated IGF-I or IGF-II in place of 125I-labeled ligand, coupled with detection using an

IGFBP function: IGF-dependent vs. independent actions

Based on the exquisitely high affinities of IGF-I and IGF-II for IGFBPs, which exceeds the affinity toward the IGF-IR, the IGFBPs have been viewed as proteins involved in the sequestration of ligand away from the IGF-IR. Over the last few years, this concept has changed with the emerging idea that IGFBPs have additional activities that are independent of their IGF binding [33]. A variety of sometimes paradoxical and conflicting biological effects have been reported, including both stimulation

IGFBP cell biology: cell surface receptors, internalization and nuclear targets

In addition to cell surface interactions, considerable interest has been generated by observations of nuclear targeting of IGFBPs and in identification of potential nuclear proteins as binding partners in two-hybrid screening protocols. Fluorescent derivatives of IGFBP-3 and IGFBP-5 were observed to translocate to the nucleus [57] via an importin β-dependent pathway [58]. Once in the nucleus, these IGFBPs have been proposed to regulate transcriptional processes involved in the cell death

IGFBPs and cancer

Over the last few years the role of the IGF system in cancer has become an area of considerable interest. IGFBP-3 has been defined in epidemiological studies as a negative risk factor for breast, prostate and colorectal cancers, with low serum IGFBP-3 and high IGF-I levels posing the greatest statistical risk [67]. Consistent with this anti-cancer role are findings in cell culture models that IGFBP-3 inhibits neoplastic cell growth [14], [68]. It has further been postulated that other IGFBPs

The future of IGFBP-based therapeutics

As natural antagonists of the IGFs, IGFBPs logically could be significant therapeutic agents for inhibiting IGF actions in a variety of human diseases, including cancer [19], diabetic renal, vascular, and eye disease [76], [77], and the “wet” form of age-related macular degeneration [78], [79]. To this end, a number of investigators have designed potential small molecule IGFBP-mimetics capable of complexing with IGFs and blocking their access to the IGF-IR. Deshayes et al. recently reported the

Conclusions

Over the last several years the interest in IGFBPs has evolved from a focus on their roles as carrier proteins that modulate the levels of free IGF, to interest in a variety of other biological effects. Clearly, many new and old questions remain to be answered in the field, including the three-dimensional structure of each IGFBP and the precise biochemistry of their interactions with IGFs, with extra-cellular matrix proteins, with putative receptors, and with intracellular targets. The

Acknowledgements

This work was supported by NIH Grant CA78887 and DoD Grant GC-3532-03-42153CM awarded to Hollings Cancer Center.

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