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Insulin-like growth factors, receptors, and binding proteins
The insulin-like growth factors (IGFs) are polypeptides with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "axis") consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (IGF-I and IGF-II), a family of six high-affinity IGF binding proteins (IGFBP 1-6), as well as associated IGFBP degrading enzymes, referred to collectivly as proteases.
IGF1/GH Axis
The IGF "axis" is also commonly referred to as the Growth Hormone/IGF1 Axis. Insulin-like growth factor 1 (IGF-1) is mainly secreted by the liver as a result of stimulation by growth hormone (hGH). IGF1 is important for both the regulation of normal physiology, as well as a number of pathological states, including cancer. The IGF axis has been shown to play roles in the promotion of cell proliferation and the inhibition of cell death (apoptosis). IGF-II is thought to be a primary growth factor required for early development while IGF-I expression is required for achieving maximal growth. Gene knockout studies in mice have confirmed this, though other animals are likely to regulate the expression of these genes in distinct ways. While IGF-2 may be primarily fetal in action it is also essential for development and function of organs such as the brain, liver and kidney.
IGF Targets
Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.
IGF-II is secreted by the brain, kidney, pancreas and muscle in mammals. It is more specific in action than IGF-1. In adult humans it is found at 600 times the concentration of insulin.
IGF Receptors
Further work is required to determine the main receptors used by these growth factors to elicit their effects. The IGF's are known to bind the IGF-1 receptor, the insulin receptor, the IGF-2 receptor, the insulin-related receptor and possible other receptors. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning the receptor signals by causing the addition of a phosphate molecule on particular tyrosines. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor" - it activates no intracellular signalling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signalling.
IGF Binding Proteins
IGF-1 and IGF-II are regulated by a family of proteins known as the IGF-Binding Proteins. These proteins help to modulate IGF action in complex ways that involve both inhibiting IGF action by preventing binding to the IGF-1 receptor as well as promoting IGF action possibly through aiding in delivery to the receptor and increasing IGF half-life. Currently, there are 6 characterized IGF Binding Proteins (IGFBP1-6). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs.
Diseases affected by IGF
Studies of recent interest show that the Insulin/IGF axis play an important role in aging. Nematodes, fruit-flies and other organisms have an increased life span when the gene equivalent to the mammalian insulin is knocked out. It is somewhat difficult to relate this finding to the mammal, however, becaue in the lower organism there is only one gene that is "insulin-like" or "IGF-1-like", whereas in the mammal insulin and IGF-1 have distinct roles. Therfore it is an open question as to whether either IGF1 or insulin in the mammal may perturb aging. Clearly the IGF/Insulin axis has an ancient evolutionary origin. Other studies are beginning to uncover the important role the IGFs play in diseases such as cancer and diabetes, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells1-3. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.
See also
References
- Cohen, Pinchas, et al. "Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial". Journal of Clinical Endocrinology and Metabolism, Vol. 73, No. 2, 1991, pp. 401-07
- Lippman, Marc E. "The development of biological therapies for breast cancer". Science, Vol. 259, January 29 1993, pp. 631-32
- Papa, Vincenzo, et al. "Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer". Cancer Research, Vol. 53, 1993, pp. 3736-40
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