Insulin-like growth factors (IGF)-1 and IGF-2 are ubiquitously expressed peptides with sequence homology to insulin.
IGFs interacts with a specific receptor on the cell membrane, namely, the IGF-I receptor (IGF-IR), and the interaction is regulated by a group of specific binding proteins. All of these molecules are considered to be members of the IGF family, which includes the polypeptide ligands IGF-I and IGF-II, two types of cell membrane receptors (i.e., IGF-IR and IGF-IIR), and six IGF-binding proteins (i.e., IGFBP-1 through IGFBP-6).
IGF-I and IGF-II are single-chain polypeptides. The two molecules have 62% homology in their amino acid sequences. The molecules share additional structural similarities, and their structures resemble the structure of proinsulin1. IGF I consists of 70 amino acid residues, IGF I1 of 67, grouped into domains A and B (similar to insulin), C (analogous to the connecting peptide of proinsulin) and D (not present in insulins). The three intrachain disulfide bridges in IGF 1 and I1 have shown to be located in analogous positions to those in (pro) insulin1.
The primary structures of mammalian IGFBPs appear to contain three distinct domains of roughly equivalent sizes: the conserved N-terminal domain, the highly variable midregion, and the conserved C-terminal domain.N-terminal domain contains 80–93 amino acid residues after the signal. Ten to 12 of the 16–20 cysteines found in the prepeptides are located within this domain. In IGFBP-1 to -5, these 12 cysteines are fully conserved, whereas in IGFBP-6, 10 of the 12 cysteines are invariant2.Midregion ranging in size from 55 amino acid residues to 95 amino acids separates the N-terminal domain from the C-terminal domain. The amino acid sequence for each midsegment appears to be unique to the protein. C-terminal region are highly conserved and, 6 cysteines of the total 16–20 cysteines are found in the C terminus and are strictly conserved2.
Both IGF-IR and IGF-IIR are glycoproteins and are located on the cell membrane. IGF-IR is a tetramer of two identical a-subunits and two identical ß-subunits. Structurally, IGF-IR resembles the insulin receptor, and there is 60% homology between them. IGF-IIR is monomeric. Three ligand-binding regions are found in the extracellular domain of the receptor, one for IGF-II binding and two for proteins containing mannose-6-phosphate (M6P), including renin, proliferin, thyroglobulin, and the latent form of (TGF)-ß transforming growth factor2.
Mode of Action
Binding of IGFs to IGF-IR activates the receptor's tyrosine kinase activity, which triggers a cascade of reactions. Two distinct signal transduction pathways have been identified for IGF-IR. One pathway activates Ras protein, Raf protein, and mitogen-activated protein kinase, and the other pathway involves phosphoinositol-3-kinase. IGF-IR is involved in cell transformation. In vitro experiments have shown that removal of IGF-IR from the cell membrane by eliminating the IGF-IR gene, by suppressing its expression, or by inhibiting its function can abolish cell transformation3. IGFBPs have multiple and complex functions. IGFBPs are able to inhibit or to enhance the action of IGFs, resulting in either suppression or stimulation of cell proliferation. These opposing effects of IGFBPs on IGFs are determined by the molecular structures of the binding proteins. When binding to IGFs, IGFBPs play three major roles: 1) transporting IGFs, 2) protecting IGFs from degradation, and 3) regulating the interaction between IGFs and IGF-IR. Normally, IGFBPs have higher binding affinity to IGFs than does IGF-IR; therefore, binding of IGFBPs to IGFs blocks the interaction between IGFs and IGF-IR and suppresses IGF action. However, binding of IGFBPs to IGFs also protects IGFs from proteolytic degradation, and that protection can enhance the action of IGFs by increasing their bioavailability in local tissue3.
Direct Involvement in Cancer - IGF-I and IGF-II are strong mitogens for a wide variety of cancer cell lines. Animal experiments indicate that overexpression of IGF-I increase the likelihood of tumor development in certain tissues. The effects of IGFs on cancer cells are mediated through IGF-IR. Eliminating IGF-IR from the cell membrane, blocking the interaction of IGFs with IGF-IR, or interrupting the signal transduction pathway of IGF-IR can abolish the mitogenic action of IGFs on cancer cells. IGF-IR is overexpressed in certain cancers, and its overexpression is associated with aggressive tumors. A recent study indicates that the insulin receptor is involved in mediating the actions of IGF-II on breast cancer. Cancer cells with a strong tendency to metastasize have higher expression of IGF-II and IGF-IR than those with a low ability to do so.In cancer, IGFBPs regulate the action of IGFs. In most situations, the binding proteins suppress the mitogenic action of IGFs and promote apoptosis. It has been shown that IGFBP-3 inhibited breast cancer cell growth without interacting with IGFs4.
IGF I protects and rescues hippocampal neurons against ß-amyloid- and human amylin-induced toxicity - Insulin-like growth factors (IGF-I and IGF-II) are well known trophic factors and their specific receptors are uniquely distributed throughout the brain, being especially concentrated in the hippocampal formation. IGFs possess neurotrophic activities in the hippocampus, an area severely affected in Alzheimer disease. There is evidence that ß-amyloid (aß)-derived peptides likely play an important role in the neurodegenerative process observed in Alzheimer disease, it has been shown that IGFs can be neuroprotective to hippocampal neurons against toxicity induced by amyloidogenic derivatives5.
1. Daughaday WH, Rotwein P (1989). Insulin-like growth factors I and II - Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev, 10:68–91.
2. Jones JI, Clemmons DR (1995). Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev., 16:3–34.
3. Clemmons DR (1997). Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev, 8:45–62.
4. Yu H, Rohan T (2000). Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression. Journal of the National Cancer Institute., 92 (18):1472-1489.
5. Doré S, Kar S, Quirion R (1997). Insulin-like growth factor I protects and rescues hippocampal neurons against ß-amyloid- and human amylin-induced toxicity. Proc. Natl. Acad. Sci, 94:4772–4777.
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