IGF-1 is a single chain peptide consists of 70 amino acids in four domains, B, C, A and D. The A- and B-domains are structural homologs of the insulin A- and B-chains with 50% sequence similarity and domain C is the analogous to the connecting C-peptide in proinsulin, and the D domain in not found in insulin.
Pituitary growth hormone (GH) as well as insulin stimulates the biosynthesis of IGF-1 in the liver and in the other organs and tissues which circulates at high concentration in blood. The IGF-1 synthesis is higher during postnatal development. During puberty, the serum level of IGF-1 increases by 2-3 fold in both male and female and this is due to the increase in the pulsatile secretion of GH and increase in sex steroid. IGF-1 act as endocrine hormone via the blood and as paracrine and autocrine growth factor locally.
In contrast to insulin that freely circulates in the blood stream, the IGFs circulate in complexes with IGF-binding proteins (IGFBPs). The level of free IGF-1 in the plasma is controlled by a family of six high affinity IGF binding proteins (IGFBPs-1 to -6) which are proteins of about 30 kDa. The IGFBPs regulate the interaction of IGF-1 with its receptor IGF-1R by binding 99% of the circulating IGF. In human about 80% of circulating IGF-1 is carried by IGFBP-3/acid labile subunit complex. All IGFBPs inhibit IGF action by sequestering IGFs and some of IGFBPs (IGFBP-1, -3 and -5) can also potentiate IGF action. A fine balance of IGF level is required for normal growth and this is achieved by the availability of free IGF which is regulated by IGFBPs. In tissues, IGF is released from its complex with IGBPs by either proteolysis of IGFBPs or binding of IGBPs to extracellular matrix. The abnormal changes in the level of circulating IGF-1 can lead to growth abnormalities such acromegaly due to overproduction of GH which increases the level of IGF-1. On the other hand, a low level of IGF-1 resulting from an inactive GH receptor leads to Laron dwarfism.
The polypeptide hormone IGF-1 binds to a number of cell surface receptors such as IGF receptor type 1 and 2 (IGF-1R, IGF-2R) and IR with different affinities. This also explains that there is not only structural similarity between the IGF ligands and insulin but there is also significant similarity between the IGF-1R and the IR which results in cross-talk between the two systems. IGF-1R can pair with either isoforms of IR (IR-A and IR-B) to form functional hybrid receptors which their role in cellular response is not clear.
IGF-1 binding to the extracellular α-subunit leads to conformational change resulting in tyrosine phosphorylation of the intracellular β-subunits, which causes an increase in the intrinsic kinase activity of the receptor which brings about various cellular responses. The cellular responses are the results of stimulation of multiple intracellular signalling pathways which regulate cell proliferation and survival. The key downstream signalling pathways include mitogen activated protein kinase (MAPK), extracellular signal regulated kinase (ERK) and phophatidylinositide-3-kinase (PI3-K)/Akt-1. Various studies such alanine scanning mutagenesis, antibody studies and receptor chimeras have shown that IGF-1 binds to its receptor using several residues located on the opposite surface of the molecule. Activation of IGF-1R by IGF-1 binding leads to a cascade of signalling networks which results in various cellular responses, such as cell proliferation, differentiation, migration and protection from apoptosis.
IGF-2 is a single-chain polypeptide with 67 amino acids, the primary source of which is reported to be the liver. The tertiary structure of IGF-2 has been determined by NMR spectroscopy and is very similar to that of IGF-1. It, too, has four domains (A-D); the B and A domains of IGF-2 have 50% sequence similarity to the B- and A-chains of insulin. The three intramolecular disulfide bonds are in analogous positions to those in pro-insulin.
IGF-2 is usually paternally expressed in the foetus and placenta and is crucial for placental development and foetal growth. The synthesis of IGF-2 is growth hormone-independent and it is mainly expressed during foetal development. The IGF II gene (Igf2) is transcribed from four different promoters (P1-P4), of which only the P1 promoter is expressed biallelically. In contrast, the other promoters contains CpG dinucleotides which are targets of methylation and hence are subjected to imprinting such that only one allele is expressed. Various forms of IGF-2 are expressed with different molecular weights; however, the most active form which binds IGF receptors is 7.5 kDa.
Like IGF-1, IGF-2 also binds to a number of cell surface receptors with different affinities. It binds to type 2 IGF receptor (IGF-2R) and IR-A with high affinity, with intermediate affinity to IR-B, and with low affinity to IGF-1R. It can also bind to a heterodimer of IR-A/IGF-1R. IGF-2R is also known as cation-independent mannose-6-phosphate receptor (IGF-2R/M-6-P) which is structurally and functionally different from IGF-1R. Unlike IGF-1R, IGF-2R is a monomeric membrane spanning glycoprotein with a 15 repeating extracellular domains (containing one binding site for IGF-2 and two binding sites for M-6-P), a 23 amino acid transmembrane domain and a 163 amino acid intracellular region. IGF-2R binds IGF-1 and IGF-2 with low and high affinities respectively and it does not bind insulin. IGF-2R does not have intracellular signalling domain unlike IGF-1R, therefore, it has no intrinsic signalling transduction capability and its main role is to bind and internalize IGF-2 which is then degraded and in this way it clears the IGF-2 from the circulation. IGF-2R also binds other ligands such as protein containing M-6-P, which is critical in mediating cell proliferation, and lysosomal enzymes. Similar to IGF-1, IGF-2 also binds to IGFBPs, preferentially IGFBP2 and 6. IGF-2 has a key physiological role in muscle and bone development and is crucial for placental development and foetal growth. There is evidence that IGF-2 may be involved in tumour growth and progression as it has been shown to increase tumour cell proliferation in cell culture.
Shabanpoor, F., Separovic, F., & Wade, J. D. (2009). The human insulin superfamily of polypeptide hormones. Vitamins & Hormones, 80, 1-31.