Abstract
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.
Highlights
Four transmembrane tyrosine kinases constitute the ErbB receptor family: the epidermal growth factor (EGF) receptor, ErbB-2, ErbB-3, and ErbB-4
EGF-dependent Tyrosine Kinase Activity of Chimeric Receptors—Receptor autophosphorylation is necessary for EGF-induced endocytosis of the EGF receptor, including AP-2 association [15, 16], 125I-EGF internalization [11], and receptor down-regulation and degradation [11]
These results demonstrate that the chimeric receptors are EGF-dependent tyrosine kinases
Summary
Vol 271, No 9, Issue of March 1, pp. 5251–5257, 1996 Printed in U.S.A. All ErbB Receptors Other Than the Epidermal Growth Factor Receptor Are Endocytosis Impaired*. EGFresponsive 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. We have measured the internalization and AP-2 association capacities of all four members of the EGF receptor family, including ErbB-3 and ErbB-4, which have not been described previously. We have used both chimeric receptors, containing an EGF receptor extracellular domain with each of the ErbB cytoplasmic domains, as well as the wild-type.
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