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IGFs thus play an essential role in many facets of reproductive function. Traditionally, therapeutic intervention in reproductive disorders at a molecular level has relied almost exclusively upon administration of gonadotrophins or LHRH (luteinizing hormone releasing hormone; Chapter 8). Because of their widespread reproductive effects, IGFs may yet prove a valuable adjunct therapy in some instances.
Neuronal and other effects
IGF-1 is widely expressed in the CNS. IGF-2 is also present, being produced mainly by tissues at vascular interfaces with the brain. Both growth factors, along with insulin, play a number of important roles in the nervous system. They stimulate the growth and development of various neuronal populations and promote neurotrophic effects (discussed later).
IGF-1 promotes differentiation of various neuronal cells, playing a central role in fostering neurite outgrowth and synapse formation, as well as myelin formation. In addition to affecting neuronal development and maintenance, it may also stimulate regeneration of damaged peripheral neurons. This activity has prompted investigation of the therapeutic potential of IGFs (particularly IGF-1) in the treatment of some neurodegenerative conditions most notably amyotrophic lateral sclerosis (ALS), which is also called motor neuron disease (MND) in the USA (strictly speaking, these two terms are not interchangeable, owing to slight differences in their pathogenicities). ALS (and MND) are caused by a progressive degeneration of specific motor neurons stretching out from the spinal cord. This leads to wasting of the muscle cells the motor neurons normally enervate. Remission is unknown, and death is the usual outcome. Clinical application of IGFs may be tempered by side effects. High-dose administration can induce hypoglycaemia, hypotension and arrhythmias.
EPIDERMAL GROWTH FACTOR (EGF)
EGF was one of the first growth factors discovered. Its existence was initially noted in the 1960s as a factor present in saliva, which could promote premature tooth eruption and eyelid opening in neonatal mice. It was first purified from urine and named urogastrone, owing to its ability to inhibit the secretion of gastric acid. EGF has subsequently proved to exert a powerful mitogenic effect on many cell types, and its receptor is expressed by most cells. Its influence on endothelial cells, epithelial cells and fibroblasts is particularly noteworthy, and the skin appears to be its major physiological target. It stimulates growth of the epidermal layer. Along with several other growth factors, EGF plays a role in the wound-healing process. EGF is synthesized mainly by monocytes and ectodermal cells, as well as by the kidney and duodenal glands. It is found in most bodily fluids, especially milk.
The gene coding for human EGF is located on chromosome 4. It is an extensive structure, consisting of 24 exons and giving rise to a 110 kb primary transcript. After splicing, this yields a mRNA coding for a 1208 amino acid prepro-EGF. In addition to the EGF sequence, this contains seven EGF-like domains, whose biological function remains unknown. Proteolytic processing of the larger molecule releases soluble EGF, a 6 kDa, 53 amino acid unglycosylated peptide. Mature EGF is very stable. Its 3-D structure, as revealed by nuclear magnetic
Tyrosine kinase domain
Figure 7.2. The EGF receptor. The N-terminal, extracellular region of the receptor contains 622 amino acids. It displays two cysteine-rich regions, between which the ligand binding domain is located. A 23 amino acid hydrophobic domain spans the plasma membrane. The receptor cytoplasmic region contains some 542 amino acids. It displays a tyrosine kinase domain, which includes several tyrosine autophosphorylation sites, and an actin-binding domain that may facilitate interaction with the cell cytoskeleton
resonance (NMR) studies, exhibits two stretches of anti-parallel b-sheet. It also contains three disulphide linkages, which contribute to this stability.
The EGF receptor
The cell-surface EGF receptor also serves as the receptor for the closely related TGF-a growth factor, as discussed later. The receptor gene is located on chromosome 7. The mature product is a 170 kDa glycoprotein, possessing 11 potential glycosylation sites (Figure 7.2).
Binding of ligand appears to induce receptor dimerization, which in turn prompts receptor activation. A variety of intracellular events are then triggered, which combine to yield the characteristic growth-promoting response. These events include:
(a) Activation of the receptorís endogenous tyrosine kinase activity, which promotes autophosphorylation of several of its tyrosine residues. The phosphorylated residues represent docking sites for several cytoplasmic proteins, including a phospholipase C. Docking activates the phospholipase C, which in turn catalyses degradation of the membrane lipid phosphoinositol bisphosphate (PIP2). This yields two well known cellular second messengers: