The EGFR (epidermal growth factor receptor) plays a key role in the regulation of essential normal cellular processes and in the pathophysiology of hyperproliferative diseases such as cancer. Recent investigations have demonstrated that GPCRs (G-protein-coupled receptors) are able to utilize the EGFR as a downstream signalling partner in the generation of mitogenic signals. This cross-talk mechanism combines the broad diversity of GPCRs with the signalling capacities of the EGFR and has emerged as a general concept in a multitude of cell types. The molecular mechanisms of EGFR signal transactivation involve processing of transmembrane growth factor precursors by metalloproteases which have been recently identified as members of the ADAM (adisintegrin and metalloprotease) family of zinc-dependent proteases. Subsequently, the EGFR transmits signals to prominent downstream pathways, such as mitogen-activated protein kinases, the phosphoinositide 3-kinase/Akt pathway and modulation of ion channels. Analysis of GPCR-induced EGFR activation in more than 60 human carcinoma cell lines derived from different tissues has demonstrated the broad relevance of this signalling mechanism in cancer. Moreover, EGFR signal transactivation was linked to diverse biological processes in human cancer cells, such as cell proliferation, migration and anti-apoptosis. Together with investigations revealing the importance of this GPCR–EGFR cross-talk mechanism in cardiac hypertrophy, Helicobacter pylori-induced pathophysiological processes and cystic fibrosis, these findings support an important role for GPCR ligand-dependent EGFR signal transactivation in diverse pathophysiological disorders.
Abbreviations used: ADAM, adisintegrin and metalloprotease; ET-1, endothelin-1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; GPCR, G-protein-coupled receptor; HB-EGF, heparin-binding epidermal growth factor; LPA, lysophosphatidic acid; MAPK, mitogen-activated protein kinase; TGF-α, transforming growth factor α; TMPS, triple membrane-passing signal; TACE, tumour necrosis factor-α-converting enzyme; PKC, protein kinase C.
Present address: Genentech, Inc., Department of Immunology, South San Francisco, CA 94080, U.S.A.
679th Meeting of the Biochemical Society held at the University of Essex, Colchester, 2–4 July 2003