Baulida J, Kraus M H, Alimandi M, Di Fiore P P, Carpenter G
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
J Biol Chem. 1996 Mar 1;271(9):5251-7. doi: 10.1074/jbc.271.9.5251.
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.
四种跨膜酪氨酸激酶构成了ErbB受体家族：表皮生长因子（EGF）受体、ErbB-2、ErbB-3和ErbB-4。我们已经测量了EGF受体家族所有四个成员的内吞能力，包括之前未被描述过的ErbB-3和ErbB-4。我们使用了包含EGF受体胞外结构域和不同ErbB胞质结构域的EGF反应性嵌合受体（EGFR/ErbB）。检测了这些生长因子-受体复合物介导125I-EGF内化、受体下调、受体降解以及与AP-2共免疫沉淀的能力。与EGF受体不同，所有EGFR/ErbB受体在配体诱导的快速内化、下调、降解以及与AP-2结合方面均受损。此外，我们分析了这里调节蛋白反应性野生型ErbB-4受体，它不介导125I-这里调节蛋白的快速内化，不显示这里调节蛋白调节的受体降解，并且不能与AP-2形成结合复合物。尽管EGF和ErbB-4受体在配体诱导的受体运输方面存在显著差异，但EGF和这里调节蛋白在刺激静止细胞中的DNA合成方面具有同等能力。这些结果表明，令人惊讶的是，EGF受体的配体依赖性下调机制并非任何其他已知ErbB受体家族成员所具有的特性。由于内吞作用被认为是生长因子-受体复合物的一种衰减机制，这些数据意味着在一个结构相关的受体家族中存在衰减机制的显著差异。
