DIVERSIFICATION OF NEU DIFFERENTIATION FACTOR AND EPIDERMAL GROWTH-FACTOR SIGNALING BY COMBINATORIAL RECEPTOR INTERACTIONS

The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respec tively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrins ic tyrosine kinase of ErbB-3 is catalytically impaired. By using inter leukin-3-dependent cells that ectopically express the three ErbB prote ins or their combinations, we found that ErbB-3 is devoid of any biolo gical activity but both ErbB-1 and ErbB-2 can reconstitute its extreme ly potent mitogenic activity. Transactivation of ErbB-3 correlates wit h heterodimer formation and is reflected in receptor phosphorylation a nd the transregulation of ligand affinity, Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are mo re potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes, Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when th e two receptors are coexpressed. Although all receptor combinations ac tivate the mitogen-activated protein kinases ERK and c-Jun kinase, the y differ in their rate of endocytosis and in coupling to intervening s ignaling proteins, It is conceivable that combinatorial receptor inter actions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-de fective ErbB-3.