Regulation of the Epidermal Growth Factor Receptor by Multi-site Phosphorylation

Abstract

Epidermal growth factor (EGF) is a small polypeptide mitogen that binds to specific receptors expressed at the surface of responsive cells. These receptors consist of a transmembrane glycoprotein with an extracellular domain that binds EGF and a cytoplasmic domain with intrinsic tyrosine kinase activity. Treatment of cells with EGF causes an increase in the receptor tyrosine kinase activity. This increased tyrosine phosphorylation initiates a cascade of signal transduction pathways that lead to cellular proliferation. The mechanism of activation of the receptor is mediated by an allosteric process that involves dimeric receptor complexes. The function of the EGF receptor is also regulated in vivo by phosphorylation at several sites by protein serine/threonine kinases that are activated by following treatment of cells with EGF. The EGF receptor is therefore an allosteric enzyme that is regulated by multi-site phosphorylation. Significantly, these allosteric and covalent regulatory mechanisms are altered in the presence of sphingolipids. Thus, endogenous sphingolipids represent putative physiological modulators of the function of the EGF receptor. In this review, the results of recent studies designed to test the hypothesis that sphingolipids regulate the signaling function of the EGF receptor are summarized. © 1993, FCCA(Forum: Carbohydrates Coming of Age). All rights reserved.