Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage.

The four members of the ErbB family of receptor tyrosine kinases (RTKs) mediate a variety of cellular responses to epidermal growth factor (EGF)-like growth factors, and serve as a model for the generation of both diversity and specificity in RTK signaling. Previous studies indicate that receptor-receptor interactions figure prominently in signaling through ErbB receptors. In addition to a role in receptor kinase activation, ligand-induced ErbB receptor homo- and heterodimerization is thought to account for the diversity of biological responses stimulated by EGF-like growth factors. Since each receptor has the potential to couple to different complements of signaling pathways, EGF-like ligands specify cellular response by dictating which pairs of receptors become activated. More recently evidence has been uncovered for ligand discrimination by individual ErbB receptor dimers; receptors appear to realize which ligand is binding and differentially respond through autophosphorylation site usage. These observations indicate that ligand stimulation of RTKs is not generic, and point to another layer in the ErbB signal diversification mechanism. The mechanistic implications of ligand discrimination are discussed.