Four transmembrane tyrosine kinases constitute the ErbB receptor family: the epidermal growth factor (EGF) receptor, ErbB-2, ErbB-3, and ErbB-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 been 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 factor-receptor complexes to mediate 125I-EGF internalization, receptor down-regulation, receptor degradation, and receptor co-immunoprecipitation with AP-2 was assayed. In contrast to the EGF receptor, all EGFR/ErbB receptors show impaired ligand- induced rapid internalization, down-regulation, degradation, and AP-2 association. Also, we have analyzed the heregulin-responsive wild-type ErbB- 4 receptor, which does not mediate the rapid internalization of 125I- heregulin, demonstrates no heregulin-regulated receptor degradation, and fails to form association 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 in quiescent cells. These results show that the ligand-dependent down-regulation mechanism of the EGF receptor, surprisingly, is not a property of any other known ErbB receptor family member. Since endocytosis is thought to be an attenuation mechanism for growth factor-receptor complexes, these data imply that substantial differences in attenuation mechanisms exist within one family of structurally related receptors.
|Titolo:||All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired|
DI FIORE, PIER PAOLO (Penultimo)
|Parole Chiave:||3T3 Cells; Animals; Receptor, erbB-3; Carrier Proteins; Receptor, erbB-2; Receptor, Epidermal Growth Factor; Epidermal Growth Factor; Humans; Neuregulin-1; Recombinant Fusion Proteins; Neuregulins; Mice; Polymerase Chain Reaction; Endocytosis; Base Sequence; Proto-Oncogene Proteins; Down-Regulation; Transfection; Kinetics; DNA Primers; Molecular Sequence Data; Glycoproteins; DNA Replication|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||1-mar-1996|
|Digital Object Identifier (DOI):||10.1074/jbc.271.9.5251|
|Appare nelle tipologie:||01 - Articolo su periodico|