IGF-Binding Proteins: Why Do They Exist and Why Are There So Many?

Abstract

Insulin-like growth factors (IGFs) are key growth-promoting peptides that act as both endocrine hormones and autocrine/paracrine growth factors. In the bloodstream and in local tissues, most IGF molecules are bound by one of the members of the IGF-binding protein (IGFBP) family, of which six distinct types exist. These proteins bind to IGF with an equal or greater affinity than the IGF1 receptor and are thus in a key position to regulate IGF signaling globally and locally. Binding to an IGFBP increases the half-life of IGF in the circulation and blocks its potential binding to the insulin receptor. In addition to these classical roles, IGFBPs have been shown to modulate IGF signaling locally under various conditions. Although members of the IGFBP family share significant sequence homology, they each have unique structural features and play distinct roles. These IGFBP genes also have different modes of regulation and distinct expression patterns. Some IGFBPs have been found to bind to their own receptors or to translocate into the interior compartments of cells where they may execute IGF-independent actions. In spite of this functional and regulatory diversity, it has been puzzling that loss-of-function studies have yielded relatively little information about the physiological functions of IGFBPs. In this review, we suggest that evolution has tended to retain an array of IGFBPs in order to facilitate fine-tuning of IGF signaling. We explore the emerging explanation that many IGFBP functions have evolved to allow the targeted adjustment of IGF signaling under stressful or irregular conditions, which would likely not be revealed in a standard laboratory setting.

Keywords: evolution; insulin-like growth factor; insulin-like growth factor 1 receptor; insulin-like growth factor signaling; insulin-like growth factor-binding protein.

Figure 1

(A) Domain structure of insulin-like growth factor-binding proteins (IGFBPs). IGFBPs contain conserved N- and C-terminal domains and a variable linker domain between them. The N-domain contains an insulin-like growth factor (IGF)-binding motif and the C-domain contains a thyroglobulin type-I repeat. The N-domain usually contains 12 conserved cysteine residues and the C-domain contains 6. (B) In extracellular environments, most IGFs are bound with IGFBPs, either in a binary complex containing one IGF and one IGFBP or a ternary complex consisting of an IGF, IGFBP-3 (or less often IGFBP-5), and a glycoprotein called acid labile subunit (ALS).

Figure 2

Different modes of Insulin-like growth factor-binding protein (IGFBP) actions. (A) Inhibition of insulin-like growth factor (IGF) signaling by sequestering IGFs away from the IGF-1 receptor (IGF1R). (B) Promotion of IGF signaling by proteolytic cleavage of the IGFBP and liberation of IGFs from the IGF/IGFBP complex for binding to the IGF1R. (C) Enhancement of IGF signaling by concentrating IGF locally and increasing IGF availability for binding to the IGF1R. (D) IGF-independent actions. Some IGFBPs have been shown to be capable of translocating into the nucleus in certain cells and may affect gene transcription directly or indirectly. Some IGFBPs have been found to bind to cell surface proteins that may act as IGFBP receptors.

Figure 3

Schematic representation of a proposed scenario of the insulin-like growth factor-binding protein (IGFBP) family evolution. A single ancestral IGFBP gene was duplicated in an early chordate. This duplication was followed by two successive rounds of chromosomal duplications or tetraploidization events in early vertebrates. Of the eight IGFBPs that resulted from this process, two were subsequently lost, leaving six types of IGFBPs that are seen in modern vertebrates.

Figure 4

Major attributes of insulin-like growth factor-binding proteins (IGFBPs) that may help to give rise to the increased flexibility and versatility in their abilities to regulate insulin-like growth factor (IGF) actions.