The Insulin-Like Growth Factor System in the Human Pathology

Insulin-like growth factors are single chain polypeptides. There are two principle IGFs referred to as IGF-I and IGF-II. IGF-1 is a polypeptide hormone with a molecular weight of 7.6-kDa structurally similar to insulin. In 1957, it is identified by Salmon and Daughaday. Because of the its ability to stimulate the sulfation of the cartilage proteoglycans, it was regarded as a sulphation factor [1]. The IGF-1 gene is on the long arm of chromosome 12q23– 23. IGF-1 gene contains 6 exons [2, 3]. The alternate extension peptide at carboxy terminal, encoded by exons 5 and 6 determines the subforms of IGF-1: IGF-1B and IGF-1A. The most abundant isoform of the IGF-1 (153 aminoacid) is IGF-1A [4, 5]. IGF1B peptide (195 amino acids) is a less abundant IGF1 isoform. IGF-2 is also a peptide with 67 amino acids and molecular weight of 7.4-kDa. IGF-2 is encoded by a gene on the short arm of chromosome 11 at position 15.5. This gene consists of nine exons [6]. In the plasma, 99% of IGFs are bound to a family of binding cysteine-rich proteins. There are six binding proteins (IGFBP-1 to IGFBP-6) [7]. They act as carriers for IGFs in the circulation, regulate the bioavailability of IGFs to spesific tissues and modulates the biological activities of IGF proteins. Six IGFbinding proteins (IGFBPs) can inhibit or enhance the actions of IGFs [8]. Potentiation of IGF activity by some of the IGFBPs, described for IGFBP-1 and IGFBP-3, is also documented for IGFBP-5. Each of IGFBPs is the product of a seperate gene. These genes share a common structural organization in which four conserved exons are located within genes ranging from 5 kb (IGFBP-1) to more than 30 kb (IGFBP-2 and IGFBP-5) [9]. IGFBPs contain N terminal and C terminal domains which are similar in aminoacid sequence. Post-translational modifications of IGFBP, including glycosylation, phosphorylation and proteolysis modify the affinities of the binding proteins to IGF. IGFs mediate their action on target cells by three