Levkowitz G, Klapper L N, Tzahar E, Freywald A, Sela M, Yarden Y
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 1996 Mar 7;12(5):1117-25.
The ErbB family of transmembrane tyrosine kinases includes the receptor for EGF (ErbB-1), two receptors for NDF/heregulin (ErbB-3 and ErbB-4) and an orphan receptor (ErbB-2). In order to examine the possibility that distinct signal transduction pathways are coupled to each ErbB protein, we examined the interaction of individual ligand-stimulated receptors with the c-Cbl protein, a protooncogene-encoded signaling molecule previously identified in hematopoietic cells. We report that c-Cbl undergoes rapid and sustained phosphorylation on tyrosine residues upon stimulation of fibroblast and epithelial cell lines with ligands of ErbB-1. By contrast, activation of either ErbB-3 or ErbB-4 by NDF did not affect tyrosine phosphorylation of c-Cbl. Likewise, activation of a chimeric ligand-stimulatable ErbB-2 by a heterologous ligand was ineffective. Despite rapidity of the EGF effect, we observed no association of c-Cbl with activated ErbB-1, implying that the interaction is indirect. Our in vitro experiments suggest that a candidate mediator of the interaction is the Grb-2/Ash adaptor protein, which is constitutively bound to c-Cbl. These results indicate that different ErbB proteins can couple to distinct signaling pathways, and therefore their physiological functions are probably non-redundant.
跨膜酪氨酸激酶的表皮生长因子受体（ErbB）家族包括表皮生长因子（EGF）的受体（ErbB-1）、神经分化因子/神经调节蛋白（NDF/heregulin）的两种受体（ErbB-3和ErbB-4）以及一种孤儿受体（ErbB-2）。为了研究不同的信号转导途径与各ErbB蛋白偶联的可能性，我们检测了单个配体刺激的受体与c-Cbl蛋白的相互作用，c-Cbl蛋白是一种原癌基因编码的信号分子，先前在造血细胞中已被鉴定。我们报告，在用ErbB-1的配体刺激成纤维细胞和上皮细胞系后，c-Cbl的酪氨酸残基会迅速且持续地发生磷酸化。相比之下，NDF对ErbB-3或ErbB-4的激活并不影响c-Cbl的酪氨酸磷酸化。同样，异源配体对嵌合的可被配体刺激的ErbB-2的激活也无效。尽管EGF的作用迅速，但我们未观察到c-Cbl与激活的ErbB-1相关联，这意味着这种相互作用是间接的。我们的体外实验表明，相互作用的一个候选介质是Grb-2/Ash衔接蛋白，它与c-Cbl组成性结合。这些结果表明，不同的ErbB蛋白可与不同的信号转导途径偶联，因此它们的生理功能可能并非冗余。
