The epidermal growth factor receptors and their family of ligands: Their putative role in atherogenesis
Introduction
The initiation and development of the atherosclerotic plaque is driven by the interaction between several growth factors and cytokines that stimulate cell migration, proliferation and activation (reviewed by Ross in 1993 [1]). The cellular response to these factors is predicated by the presence of appropriate receptors on cells involved in atherogenesis. These cells include vascular smooth muscle cells, endothelial cells and leukocytes. The latter are thought to be particularly important in the initial phases of lesion development [2], [3], [4], [5] and it is therefore likely that factors contributing to monocyte/macrophage and T cell accumulation and activation are major modulators of the process. Among the many factors implicated in atherogenesis are several ligands for the EGF receptor family. The epidermal growth factor receptor is the prototype of the type-I growth factor receptor family with tyrosine kinase activity. In this review, we will discuss the biological functions of this receptor and its ligands and their potential to modulate the function of cells involved in the atherosclerotic process.
Section snippets
The epidermal growth factor family
The EGF family consists of several peptide growth factors (Table 1) that act as ligands for the EGF family of receptors (Table 2). Among these are: epidermal growth factor (EGF), transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), epiregulin (EPR), epigen and the four neuregulins. NRG-1 is also known as Neu differentiation factor (NDF), heregulin (HRG), acetylcholine receptor-inducing activity (ARIA) and glial growth
The epidermal growth factor receptor (EGFR) family
The epidermal growth factor receptor is a 170-kDa glycoprotein and the prototype of the type-1 growth factor receptor family with tyrosine kinase activity. It is composed of a single polypeptide chain of 1186 amino acid residues that is cleaved from a 1210-residue polypeptide precursor. It is encoded by a gene located on the short arm of chromosome 7(p11.2), has 28 exons and is nearly 200 kbp in length [45]. The EGFR family consists of four members: ErbB1 (also termed EGFR, HER1), ErbB2 (also
The EGF family of ligands and their role in atherogenesis
Several EGF-related proteins are expressed by cells involved in atherogenesis (Fig. 4). They appear to mediate important biological effects relevant to the atherogenic process. For example EGF, TGFα, HB-EGF, BTC and EPR, mediate the transformation of SMCs from a differentiated non-proliferative phenotype into a dedifferentiated proliferative and migratory phenotype. This change is associated with the development and progression of atherosclerosis [153].
EGF receptor and atherosclerosis
EGF receptors have been identified immunocytochemically on intimal smooth muscle cells within human atherosclerotic plaque [174]. EGF receptors have also been demonstrated on cultured rat aortic smooth muscle cells and can mediate both cell proliferation and DNA synthesis [178], [179]. Ligands for ErbB1, including EGF [180] and HB-EGF [16] have been shown to possess mitogenic activity for smooth muscle cells in vitro. HB-EGF is also capable of inducing smooth muscle cell migration in vitro [181]
Polymorphisms of ErbB1
Several polymorphisms have been identified in the ErbB1 gene by restriction digest [192], [193] and single strand conformation polymorphism analysis [194]. However, no functionality has yet been attributed to these polymorphisms. More recently, a CA dinucleotide repeat within intron 1 of the receptor has been found [195]. The alleles at this locus comprise from 14 to 21 tandem repeats, and it appears that ErbB1 transcriptional activity declines significantly with an increasing number of repeats
Therapeutic inhibition of the EGFR–ligand interactions
The EGF receptor family may be inhibited by a number of exogenous factors that target the external ligand-binding domain and the ATP binding site at the kinase domain. A number of potentially inhibitory compounds have been discovered over the past decade [199]. A family of receptor tyrosine kinase inhibitors (TKIs), termed tyrphostins, were designed to be competitive with the substrates of the receptor [200], [201]. These compounds were found to inhibit EGF-stimulated proliferation but they did
Conclusions
The recruitment of peripheral monocytes to the sub-endothelial space, their development into macrophages and subsequent proliferation is critical during atherosclerosis. The EGF receptor, ErbB1, has been identified on various cell types, including monocytes and macrophages, present within the atherosclerotic lesion. Upon ligand-binding, ErbB1 activation results in the activation of numerous signalling cascades that control processes including proliferation and apoptosis. Indeed, EGF, a ligand
Acknowledgements
We would like to thank the British Heart Foundation for their financial support and Dr. Shahida Shafi for her assistance in the final preparations of this manuscript.
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