THE ONCOGENIC ERBB-2 ERBB-3 HETERODIMER IS A SURROGATE RECEPTOR OF THE EPIDERMAL GROWTH-FACTOR AND BETACELLULIN/

The ErbB-1 receptor tyrosine kinase binds to six different growth fact ors, whose prototype is the epidermal growth factor (EGF). Two homolog ous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of anot her family of growth factors, the Neu differentiation factors (NDFs/ne uregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the th ree other ErbB proteins. Here we report that at high concentrations, E GF can induce cell growth and differentiation in the absence of ErbB-1 . This function is shared by betacellulin, but not by three other liga nds, including the transforming growth factor alpha (TGF alpha). The f unctional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex, When singly express ed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In additio n, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating stric t cooperativity between ErbB-3 and ErbB-2, Through analysis of chimera s between EGF and TGF alpha, we identified the middle portion of EGF ( loop B) as the site that enables activation of ErbB-2/ErbB-3. In concl usion, cooperative and promiscuous binding of stroma-derived growth fa ctors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be sig nificant to cancer development. The mechanistic implications of our re sults for a model that attributes receptor dimerization to ligand biva lency, as well as to a recently proposed mechanism of secondary dimeri zation, are discussed.