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Recent studies also point to the existence of a fourth receptor species. This appears to be a hybrid structure, composed of an insulin receptor a-b dimer crosslinked to an IGF-1 receptor a-b dimer. Although this receptor type displays a marked reduction in its affinity for insulin,
Table 7.5. The range of human IGF binding proteins (IGF BPs or ‘BPs’), and an indication of their relative affinities for ligand. AA indicates a higher affinity than A. The approximate range of IGF BP association constants (Ka) is 1 x 10 9—1 x 10710 M
IGF I IGF II
IGF BP 1 AA AA
IGF BP 2 A AA
IGF BP 3 AA AA
IGF BP 4 AA AA
IGF BP 5 AA AA
IGF BP 6 A AA
physiological concentrations of IGF-1 prompts autophosphorylation of its intracellular tyrosine kinase domain. The in vivo importance of this hybrid receptor remains to be elucidated.
IGFs typically display 5-6% of the hypoglycaemic (reduction in blood glucose concentrations) potency of insulin. As IGF serum concentrations are of the order of 1000 times higher than insulin concentrations, profound IGF-associated hypoglycaemia would be expected under normal physiological conditions. This is avoided as IGFs, found in the serum or other extracellular fluids, are invariably tightly complexed to an additional protein, termed an IGF-binding protein (IGFBP). This prevents IGF interaction with its receptors, hence preventing uncontrolled IGF activity. Six different IGFBPs have been identified (Table 7.5). Individual members of this family generally exhibit in the region of 50% homology with each other, although they vary in molecular weight from 23 kDa (BP6) to 31.5 kDa (BP2). Although they display differences in their binding affinities for IGF ligands, the IGFs appear to bind them more tightly than they do their cell surface receptors.
IGFBPs are widely expressed, but high levels of BP1 and BP2 in particular are found in the liver. The bulk of serum IGF-1 and -2 is found complexed to BP3 and an acid-labile polypeptide. The remaining molecules of serum IGFs are usually found complexed to BP1, BP2 or BP4.
The IGFBPs probably fulfil several biological functions in addition to preventing hypoglycaemia. They likely protect the mitogen (e.g. from proteolysis) in the blood, and appear to significantly increase the IGF’s plasma half-life. They also probably modulate IGF function locally at the surface of IGF-sensitive cells.
IGFs exhibit a wide range of gross physiological effects (Table 7.6), all of which are explained primarily by the ability of these growth factors to stimulate cellular growth and differentiation. Virtually all mammalian cell types display surface IGF receptors. IGFs play a major stimulatory role in promoting the cell cycle (specifically, it is the sole mitogen required to promote the G1b phase, i.e. the progression phase. Various other phases of the cycle can be stimulated by additional growth factors). IGF activity can also contribute to sustaining the uncontrolled cell growth characteristic of cancer cells. Many transformed cells exhibit very high levels of IGF
GROWTH FACTORS 283
Table 7.6. Overview of some of the effects of the IGFs
Promotes cell cycle progression in most cell types
Fetal development: promotes growth and differentiation of fetal cells and organogenesis Promotes longitudinal body growth and increased body weight Promotes enhanced functioning of the male and female reproductive tissue Promotes growth and differentiation of neuronal tissue
receptors, and growth of these cells can be inhibited in vitro by the addition of antibodies capable of blocking IGF-receptor binding.
IGF and fetal development
IGFs 1 and 2, along with insulin, play an essential role in promoting fetal growth and development. IGF-2, and its receptor is expressed by the growing embryo as early as the two-cell stage (i.e. even before implantation in the womb wall). Later, the developing embryo also begins to synthesize IGF-1 and insulin. These mitogens and their receptors are expressed in virtually every fetal tissue in a coordinated manner.
IGFs and growth
Most of the growth-promoting effects of growth hormone (GH) are actually mediated by IGF-1. Direct injection of IGF-1 into hypophysectomized animals (animals whose pituitary — the source of GH — is surgically removed) stimulates longitudinal bone growth, as well as growth of several organs/glands (e.g. kidney, spleen, thymus). Bone and surrounding connective tissue represents a rich source of IGFs and various other growth factors. IGFs (particularly IGF-1) promotes bone growth largely due to its ability to stimulate osteoblast differentiation and proliferation. Osteoblasts are the cells primarily responsible for bone formation. The initial stages of bone development are marked by the deposition of a meshwork of collagen fibres in connective tissue, followed by their cementing by polysaccharides. This is then impregnated in the final stages with crystals of calcium salts.