Overview
Until recently, insulin-like growth factors (or, as they were originally known, somatomedins) were thought to be produced in the liver in response to growth hormone, to circulate in the blood, and to mediate the effects of growth hormone (GH) on skeletal cartilage to promote bone elongation during childhood (Salmon and Daughaday 1957). Recent insights have necessitated revision of the somatomedin hypothesis in several important respects:
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1.
The insulin-like growth factor (IGF) family consists of two related polypeptides, IGF-I and IGF-II. [Peptides identical to IGF-I were initially designated somatomedin A, somatomedin C and basic somatomedin; rat IGF-II was initially designated MSA or multiplication stimulating activity (Daughaday et al. 1987 a)]. Despite similar chemical structure and in vitro activity, IGF-I and IGF-II have different in vivo activities. IGF-I is GH dependent, and fulfills many of the criteria of a somatomedin or mediator of GH action. IGF-II is minimally GH dependent, and has little effect on skeletal cartilage. It may play a role in fetal development and in the central nervous system.
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2.
The IGFs are synthesized in many tissues in fetal and adult animals. Their actions may be local (autocrine or paracrine) or endocrine (circulate to a distant target organ). Thus, the physiologically relevant IGF levels may be tissue levels rather than plasma levels.
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3.
The biological actions of IGFs are not limited to mitogenesis. They also may induce differentiation or promote the expression of differentiated functions. The precise biological response is determined by the developmental state of the cell, as well as the presence of other hormones and growth factors.
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4.
The biological actions of IGFs are potentially mediated by either of two specific receptors. The IGF-I receptor (or type I IGF receptor) contains a cytoplasmic tyrosine kinase domain, and binds both IGF-I and IGF-II. Studies with blocking antibodies to the receptor suggest that it mediates many, if not all, of the known effects of IGF-I and IGF-II. The IGF- II/Mannose-6-phosphate (Man-6-P) receptor (or type II IGF receptor) has a completely different structure. It lacks a tyrosine kinase domain, and has a small cytoplasmic domain similar to other cycling receptors. This receptor binds lysosomal proteins that contain a mannose-6-phosphate recognition marker in addition to binding IGF-II. Although it has been claimed that the IGF-II receptor mediates classic IGF actions, the structural dissimilarity from the type I receptor requires that it use a different set of signalling mechanisms.
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5.
The IGFs in blood, other extracellular fluids, and cell culture media occur complexed to specific binding proteins. At least three IGF binding proteins have been purified and cloned. The total number of binding proteins is not known. Most of the IGFs in human and rat plasma are carried in a 150-kDa GH-dependent binding protein complex. It consists of a glycosylated ligand-binding subunit (∼50-kDa) and a second acid-labile nonbinding sub-unit (∼100-kDa). Lower molecular weight binding proteins occur in fetal plasma and extracellular fluid. These are GH independent and are not glycosylated. Two distinct classes of GH-independent binding proteins have been cloned. Although the role of the IGF binding proteins is not fully understood, they have the capacity to modulate IGF action. In most cases, the IGF-binding protein complex does not bind to cell receptors and is inactive. In some cases, however, binding proteins act synergistically with IGF-I to stimulate mitogenesis. Whether these different biological activities are properties of different binding proteins or of binding proteins that have undergone different posttranslational modifications remains to be determined.
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Rechler, M.M., Nissley, S.P. (1991). Insulin-Like Growth Factors. In: Sporn, M.B., Roberts, A.B. (eds) Peptide Growth Factors and Their Receptors I. Springer Study Edition. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-3210-0_6
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DOI: https://doi.org/10.1007/978-1-4612-3210-0_6
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