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.
Acknowledgments
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