NEU DIFFERENTIATION FACTOR INHIBITS EGF BINDING - A MODEL FOR TRANSREGULATION WITHIN THE ERBB FAMILY OF RECEPTOR TYROSINE KINASES

Neu differentiation factor (NDF, or heregulin) and epidermal growth fa ctor (EGF) are structurally related proteins that bind to distinct mem bers of the ErbB family of receptor tyrosine kinases. Here we show tha t NDF inhibits EGF binding in a cell type-specific manner. The inhibit ory effect is distinct from previously characterized mechanisms that i nvolve protein kinase C and receptor internalization because it occurr ed at 4 degrees C and displayed reversibility. The extent of inhibitio n correlated with both receptor saturation and affinity of different N DF isoforms, and it was abolished upon overexpression of either EGF re ceptor or ErbB-2. Binding kinetics and equilibrium analyses indicated that NDF reduced the affinity, rather than the number, of EGF receptor s, through an acceleration of the rate of ligand dissociation and dece leration of the association rate, On the basis of co-immunoprecipitati on of EGF and NDF receptors, we attribute the inhibitory effect to the formation of receptor heterodimers. According to this model, EGF bind ing to NDF-occupied heterodimers is partially blocked. This model of n egative trans-regulation within the ErbB family is relevant to other s ubgroups of receptor tyrosine kinases and may have physiological impli cations.