The Role of Heparan Sulfate Proteoglycan in Ligand-induced Activation of the Epidermal Growth Factor Receptor.

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The class of mammalian biologically active polypeptides called growth factors influence the proliferation, differentiation, motility, maintenance and apoptosis of target cells. Growth factors such as epidermal growth factor(EGF) and fibroblast growth factor (FGF) elicit responses in cells by interacting with the extracellular domain of their receptors. This binding results in the activation of the intrinsic tyrosine kinase activity of the receptor and signaling. It has become apparent that accessory receptors, namely heparan sulfate (HS) proteoglycan, are required for the action of some growth factors. The mechanism of action of the FGFs serves as the prototype for this phenomenon. Amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), two ligands which function via the activation of the EGF receptor have been shown to require extracellular HS proteoglycan for bioactivity. The heparin-binding regions of amphiregulin and HB-EGF have been localized to a basic -20 amino acid segment which lies just adjacent to the EGF-like domain of these mitogens. Based upon experimental data, a mechanism is proposed for amphiregulin action in which the HS proteoglycan is an integral membrane protein which either presents amphiregulin to the receptor or stabilizes the bivalent binding of one molecule of amphiregulin to the activated receptor dimer.
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