ERBB-2 IS A COMMON AUXILIARY SUBUNIT OF NDF AND EGF RECEPTORS - IMPLICATIONS FOR BREAST-CANCER

Overexpression of the erbB-2 gene contributes to aggressive behavior o f various human adenocarcinomas, including breast cancer, through an u nknown molecular mechanism, The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct Ligand of Er bB-2 has been reported, We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it mag affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand, This possi bility was addressed in breast cancer cells through either overexpress ion of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody We report that ErbB-2 ov erexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates, Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by a ccelerating dissociation of both growth factors, The kinetic effects r esulted in enhancement and prolongation of the stimulation of two majo r cytoplasmic signaling pathways, namely: MAP kinase (EPK) and c-Jun k inase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan -ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF, Therefore, the oncogenic action of ErbB-2 in human cancers may b e due to its ability to potentiate in trans growth factor signaling.