All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired.
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.
Baulida
J
J
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Kraus
M H
MH
Alimandi
M
M
Di Fiore
P P
PP
Carpenter
G
G
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000494:pharmacology; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D020890:Neuregulin-1; D020880:Neuregulins; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D002352:Carrier Proteins; D017931:DNA Primers; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D020890:Neuregulin-1; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins; C087230:heregulin beta1; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse