Figure 1. The diversity of the epidermal growth factor receptor-signaling network.

The EGFR transduction cascade is a highly complex network, consisting of signaling options based on multiple layers. The ligand input and receptor engagement occurs in the extracellular layer. Receptor-specific ligands for ErbB1,ErbB3, and ErbB4 have been identified as shown. Note that no direct ligands for ErbB2 had been isolated to date. At the cell surface, receptor engagement leads to tyrosine phosphorylation and several receptor dimerization options (depicted by arrows: thick arrow denotes homodimerization and thin arrow denotes heterodimerization; the “X” in ErbB3 represents absence of the intrinsic tyrosine kinase activity). The selective activation of well-characterized signaling transduction pathways (shown in boxes), depends on the various arrangements of ligand-ErbB engagement, tyrosine phosphorylation, and subsequent receptor dimerization combinations beneath the cell surface. Finally, the output layer includes a variety of cell responses (shown in bold). J.R. Grandis, J.C. Sok / Pharmacology & Therapeutics 38 102 (2004) 37–46