A HIERARCHICAL NETWORK OF INTERRECEPTOR INTERACTIONS DETERMINES SIGNAL-TRANSDUCTION BY NEU DIFFERENTIATION FACTOR NEUREGULIN AND EPIDERMAL GROWTH-FACTOR/

The ErbB family includes four homologous transmembrane tyrosine kinase s. Whereas ErbB-1 binds to the epidermal growth factor (EGF), both Erb B3 and ErbB-4 bind to the Neu differentiation factors (NDFs, or neureg ulins), and ErbB-2, the most oncogenic family member, is an orphan rec eptor whose function is still unknown. Because previous lines of evide nce indicated the existence? of interreceptor interactions, we used ec topic expression of individual ErbB proteins and their combinations to analyze the details of receptor cross talks. We show that 8 of 10 pos sible homo- and heterodimeric complexes of ErbB proteins call be hiera rchically induced by ligand binding, Although ErbB-2 binds neither lig and, even in a heterodimeric receptor complex, it is the preferred het erodimer partner of the three other members, and it favors interaction with ErbB-3. Selective receptor overexpression in human tumor cells a ppears to bias the hierarchical relationships. The ordered network is reflected in receptor transphosphorylation, ErbE-2-mediated enhancemen t of ligand affinities, and remarkable potentiation of mitogenesis by a coexpressed ErbB-2. The observed superior ability of ErbB-2 to form heterodimers, in conjunction with its uniquely high basal tyrosine kin ase activity, mag explain why ErbB-2 overexpression is associated with poor prognosis.