INSULIN-LIKEGROWTHFACTOR-1

Discovery

In 1957, a “sulfation factor” that mediates the action of growth hormone (GH) on the incorporation of ³⁵S sulfate into a cartilage segment was discovered in rats, and named somatomedin, now known as IGF-1. IGF-1 was also identified in 1963 as nonsuppressible insulin-like activity soluble in acid/ethanol (NSILA-S). In 1978, IGF-1 was isolated from the Cohn fraction of plasma proteins together with IGF-2.

Structure

IGF-1 is a single-chain polypeptide sharing high structural homology with proinsulin (about 50%) and IGF-2 (about 70%) .1 Three disulfide bonds that are involved in the structural maintenance of the insulin family peptides are conserved. PreproIGF-1 is composed of a signal peptide and five domains; B, C, A, D, and E. The E domain is proteolytically cleaved before secretion. The aa sequence of IGF-1 is highly conserved in vertebrates. Mr ~7500, pI 8.5. Lyophilized peptide should be reconstituted in 10mM HCl. Lyophilized peptide can be stored at 2–4°C for at least 2 years.

Gene, mRNA, and precursor

The human IGF-1 gene, IGF1, location 12q23.2, consists of six exons. There are six major transcript variants that differ in promoter use, RNA splicing, and mRNA polyadenylation. These IGF-1 mRNAs are classified based on a combination of differential promoter use (Type 1 or 2) and alternative splicing of exons encoding the E domain (Ea, Eb, and Ec). However, all transcripts resulted in the same mature protein of 70 aa residues. The organization of IGF-1 genes is substantially different among vertebrates; up to 11 exons are found in Australian marsupials whereas 4–8 exons are recognized in nonmammalian vertebrates. Two nonallelic genes for igf1 have been identified in the Xenopus, zebrafish, and salmon. In the zebrafish and tilapia, a gonad-specific igf3 (or igf1b) has been identified. Viruses such as the family Iridoviridae express viral insulin/IGF-1- like peptides (VILPs). VILPs are capable of activating insulin and IGF-1 receptor signaling and may play a role in disease.

Synthesis and release

Mammalian IGF-1 genes have two promoters (P1 and P2) that lack TATA and CAAT elements. P1 is the potent major promoter, and is conserved widely in vertebrates. The proximate promoter region of the IGF-1 gene contains binding sites for liver-enriched transcription factors such as HNF-1α, C/EBPα, and C/EBPβ. GH is the primary hormone regulating the synthesis and release of IGF-1 in the liver after birth. The action of GH is mediated chiefly by the JAK2/Stat5b pathway. Several GH-inducible Stat5b binding sites have been found in introns and distal regions of the Igf1 loci. However, such GH-inducible Stat5b binding sites are absent in nonmammalian vertebrates and thus other regulatory pathways by which GH stimulates the transcription of igf1 are assumed. IGF-1 gene expression is also regulated at the transcription level by other hormones such as insulin, cortisol, and sex steroids, and by the developmental stage independently of GH action. Nutritional status regulates IGF-1 mRNA at the posttranscriptional level by affecting mRNA processing and stability.

Receptors

The receptor of IGF-1 (type 1 IGF receptor, IGF-1R) belongs to a family of the receptor tyrosine kinase (RTK) containing a single transmembrane domain, and shares high sequence homology (60%) with the insulin receptor. The human IGF-1R gene, IGF1R, location15q26.3, consists of 21 exons encoding an extracellular α-subunit (706 aa residues), which contains a ligand binding domain, and a transmembrane β-subunit (627 aa residues), which contains tyrosine kinase activity. The α- and β-subunits are synthesized as a single-chain prepropeptide and cleaved after translation, then bridged by a disulfide bond to form the IGF-1 half-receptor (αβ). Two half-receptors dimerize to form a functional IGF-1R (α2β2). The IGF-1 halfreceptor can also form a hybrid receptor with the insulin half-receptor to bind mainly IGF-1. Teleosts have two paralogs of igf1r.

Agonists and Antagonists

IGF-2, insulin, Des IGF-1, Long R3 IGF-1, LL-37, hypoxia, and Akt-induced stem cell factor (HASF) are agonists. IGFBPs, JB1, and JB3 (12-aa synthetic peptides), and M1557 (D domain analog) are antagonists.

Biological functions

IGF-1 acts on most tissues, but the liver is not a major target. IGF-1 is involved in growth and metabolism at the organismal level, and in cell proliferation, migration, differentiation, and survival at the cellular level. IGF-1 inhibits apoptosis. An important role of circulating IGF-1 is to regulate GH synthesis/secretion at the pituitary and hypothalamus through a negative feedback loop.

Clinical implications

IGF-1 deficiency is related to Laron syndrome (short stature due to GH resistance or insensitivity), liver cirrhosis, and age-related cardiovascular and neurological diseases. Epidemiologic studies suggest relationships between IGF-1 and cancer risks such as prostate, colon, and breast cancers.

Description

IGF-1 is a multifunctional polypeptide structurally related to proinsulin. IGF-1 promotes cell proliferation, differentiation, growth, migration, and survival through autocrine/paracrine and endocrine pathways. It mediates part of growth hormone actions and is essential for normal prenatal and postnatal growth.

Clinical Use

IGF-1 levels are routinely used for diagnosis in patients with suspected acromegaly or GH/IGF-1 deficiency. The US Food and Drug Administration approved recombinant human IGF-1 for the treatment of patients with severe primary IGF-1 deficiency. Due to its antiapoptotic and proliferative actions, the IGF-1 axis confers tumor cell resistance to anticancer therapy. Thus, inhibition of the IGF-1 signaling using monoclonal antibodies against IGF-1 and IGF-1R and tyrosine kinase inhibitors is a potential therapy for cancers. However, the overexpression or dysregulation of the IGF-1 axis is not the driver but rather secondary to another molecular event in tumorigenesis. Combining IGF-targeted agents with other agents may be a more effective therapeutic approach.