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Insulin-like Growth Factor (IGF) System Proteins

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Insulin-like Growth Factor (IGF) System Proteins

Insulin-like Growth Factor (IGF) System Proteins Background

Insulin-like growth factors (IGF-I and II) are important endocrine, paracrine, and autocrine mediators of physiological growth. They promote cell proliferation, survival and differentiation. Their effects are mainly mediated through the IGF-I receptor, but IGF also binds to IGF-II / mannose 6-phosphate and insulin receptors. IGF activity is regulated by six families of high-affinity IGF-binding proteins (IGFBP); in most cases, IGFBP inhibits the effects of IGF, but may also enhance their effects. It is now available for the determination of IGF-I, IGF-II and single IGFBP. IGF-1 and IGFBP-3 assays have certain practicality in the diagnosis and management of acromegaly and growth hormone deficiency. There is a wealth of in vitro and in vivo evidence supporting the pathogenesis of IGF system alterations in many diseases, including diabetes, cancer, cardiovascular disease and neuromuscular disease. Recently, epidemiological studies have linked high IGF-I levels to certain cancers and low IGF-I levels to ischemic heart disease. Preliminary studies on recombinant IGF-1 for the treatment of diabetes, osteoporosis and neuromuscular diseases have been performed in humans. In contrast, there is considerable interest in developing IGF inhibitors for the treatment of cancer. This apparent contradiction highlights the need to develop therapies with ligand and tissue specific characteristics in addition to natural ligands and inhibitors. This will only be possible as we learn more about this complex system. In addition, as IGF and IGFBP assays become more readily available, their role in disease diagnosis and surveillance should be more clearly defined in the near future.

Insulin-like Growth Factor (IGF) System Proteins Figure 1.ILGF.

IGF-I and IGF-II

IGF-I and IGF-II are ~ 7.5 kDa peptides with 67% amino acid identity. They are also highly homologous to insulin in sequence and structure. IGF-I, -II and insulin are thought to be derived from a common ancestral gene. However, although insulin is primarily a metabolic hormone.

Insulin-like Growth Factor (IGF) System Proteins Figure 2. Protein structure of IGF-I.

Nevertheless, IGF has insulin-like metabolic activity, and the molar potency of IGF-1 accounts for approximately 8% of insulin potency. IGF is synthesized by most organs and can be used as an endocrine, paracrine and / or autocrine growth factor. In most organs, IGF-I synthesis is regulated by growth hormone (GH). In particular, most circulating IGF-I comes from the liver under growth hormone control. Circulating IGF-I levels fluctuate throughout life, are relatively low in childhood, peak at puberty, and then gradually decline after adulthood. Other factors important in the regulation of IGF-I include nutritional status, sex steroids and insulin. In diseases including severe illness, poorly controlled diabetes, malnutrition, cirrhosis, and hypothyroidism, circulating IGF-I levels may be low.  IGF-II expression is largely unregulated by GH or nutritional status. In rodents, IGF-II levels are high before birth and cease to be expressed in most organs shortly after birth. In contrast, the level of IGF-II in human circulation is about four times that of IGF-I, and it does not fluctuate significantly with age.

Insulin-like Growth Factor (IGF) System Proteins Figure 3. Protein structure of IGF-2.

IGF receptor


The IGF-I receptor is composed of two disulfide-linked αβ heterodimers, and its structure is similar to that of the insulin receptor. 3,11 IGF-I and IGF-II both bind the IGF-I receptor with high affinity, and insulin binds with lower affinity.

Insulin-like Growth Factor (IGF) System Proteins Figure 4. Protein structure of IGF1R protein.

Most of the effects of IGF-1 and II are mediated by this receptor. After ligand binding, the receptor has tyrosine kinase activity, leading to autophosphorylation, recruitment of docking proteins (such as IRS-1 (insulin receptor substrate 1)) and subsequent stimulation of many signal transduction pathways, including Ras/MAP (Mitogen-activated protein) kinases, PI3 kinase/PKB (protein kinase B) Akt and PI3 kinase/mTOR (mammalian target of rapamycin) /S6K.3. Activation of these pathways results in increased cell proliferation, survival, and protein translation. The IGF-II/6-phosphate mannose (M6P) receptor is structurally different from the IGF-I and insulin receptors. 14 It binds IGF-II with high affinity, IGF-I with much lower affinity, and does not bind insulin. As the name suggests, it also incorporates M6P-containing glycoproteins and plays an important role in the sorting of lysosomal enzymes. The IGF-II/M6P receptor has a short intracellular domain. The extent to which this receptor mediates the action of IGF-II is unknown. Its main role related to IGF seems to be the internalization and elimination of IGF-II. The IGF-II/M6P receptor also binds many other ligands, including potential transforming growth factor beta (TGFβ), retinoic acid, and urokinase plasminogen activator receptors. The soluble form of this receptor was found in circulation to lack transmembrane and intracellular domains. IGF also binds to the insulin receptor, mediating some of its metabolic effects. 10 Recently, studies have shown that IGF-II, but does not bind IGF-I, is an insulin receptor isoform A that is overexpressed in certain cancers. This receptor also mediates certain proliferation effects of IGF-II.

Insulin-like Growth Factor (IGF) System Proteins Figure 5. Protein structure of IGF2R protein.

IGF-affected diseases

Recent studies have shown that the insulin/IGF axis plays an important role in aging. [Human insulin-like genes have significantly different effects, but some have less crosstalk, presumably because there are multiple insulin receptor-like proteins in the body. Simple organisms usually have fewer receptors. For example, only one insulin-like receptor is present in C. elegans. Although some suggest that dietary restriction may be related to whether mammalian IGF-1 or insulin can interfere with aging, this is an open question.

Reference:

  1. Gunnell D.; et al. ssociation of Insulin-like Growth Factor I and Insulin-like Growth Factor-Binding Protein-3 with Intelligence Quotient Among 8- to 9-Year-Old Children in the Avon Longitudinal Study of Parents and Children. Pediatrics. 2005, 116 (5): e681–6.

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