What's new in the IGF-binding proteins?

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. KeywordsInsulin-like growth factor (IGF); IGF binding protein (IGFBP); IGF-I receptor (IGF-IR); Binding site; Structure-function Historical introduction and overviewOver 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 have their own intrinsic biological activities, independent of their ability to interact with IGF-I and IGF-II. Considerable evidence has accumulated suggesting that IGFBPs directly regulate several cellular functions. What has been distilled from these studies is a broad description of both stimulatory and inhibitory actions for a given IGFBP. An in depth analysis of the literature encompassing the complete range of IGFBP actions is beyond the scope of this brief review, and the interested reader is referred to a number of recent summaries on the subject [1][2][3][4]. The focus of this mini-review will be limited to a discussion of recent advances in our understanding of IGFBP structure-function relationships, with emphasis on both new developments and new questions that have arisen in the field. 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) [5,7]. When all of these data are considered, it appears that neither the NH 2 -or COOH-terminus separately embodies the full, physiologically critical IGF binding domain. Rather, both regions contribute to high affinity IGF binding as independently organized segments that are spatially coordinated by the linker domain into the IGF binding site [9,[16][17][18].What falls out of this discussion is the question of whether one can generalize among the six IGFBPs in discussing structure-function attributes of the IGF binding pocket. For IGFBP-2, several studies indicate that its binding site is located primarily within the COOH-terminus [5,15,19,20], yet Carrick et al. [17] recentl...

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