ALL ERBB RECEPTORS OTHER THAN THE EPIDERMAL GROWTH-FACTOR RECEPTOR ARE ENDOCYTOSIS IMPAIRED

Four transmembrane tyrosine kinases constitute the ErbB receptor famil y: the epidermal growth factor (EGF) receptor, ErbB-2, ErbB-3, and Erb B-4. We have measured the endocytic capacities of all four members of the EGF receptor family, including ErbB-3 and ErbB-4, which have not b een described previously. EGF-responsive chimeric receptors containing the EGF receptor extracellular domain and different ErbB cytoplasmic domains (EGFR/ErbB) have been employed. The capacity of these growth f actor-receptor complexes to mediate I-125-EGF internalization, recepto r down-regulation, receptor degradation, and receptor co-immunoprecipi tation with AP-2 was assayed. In contrast to the EGF receptor, all EGF R/ErbB receptors show impaired ligand-induced rapid internalization, d own-regulation, degradation, and AP-2 association. Also, we have analy zed the heregulin-responsive wild-type ErbB-4 receptor, which does not mediate the rapid internalization of I-125-heregulin, demonstrates no heregulin-regulated receptor degradation, and fails to form associati on complexes with AP-2. Despite the substantial differences in ligand- induced receptor trafficking between the EGF and ErbB-4 receptors, EGF and heregulin have equivalent capacities to stimulate DNA synthesis i n quiescent cells. These results show that the ligand-dependent down-r egulation mechanism of the EGF receptor, surprisingly, is not a proper ty of any other known ErbB receptor family member. Since endocytosis i s thought to be an attenuation mechanism for growth factor-receptor co mplexes, these data imply that substantial differences in attenuation mechanisms exist within one family of structurally related receptors.