Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2
Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2
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DOI：
10.1038/sj.onc.1201595
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发表时间：
1997-10-30
期刊：
影响因子：
8
通讯作者：
Epstein, RJ
中科院分区：
文献类型：
--
作者：
Gulliford, TJ;Huang, GC;Epstein, RJ
表皮生长因子受体 (EGFR) 可被多种配体激活，包括 EGF 和转化生长因子-α (TGF α)，但尚未鉴定出同源 ErbB2 癌蛋白的配体。在这里，我们使用 ErbB2 磷酸化抗体 (aPY(1222)) 和激活特异性 EGFR 抗体来证明，低浓度的 EGF 比等摩尔的 TGF α 更能诱导 A431 细胞中 ErbB2 的酪氨酸磷酸化，而 EGFR 被 TGF α 激活更有效。共沉淀研究证实，活化的 EGFR 和转磷酸化的 ErbB2 的异二聚化很容易被 EGF 诱导，但不能被 TGF α 诱导。 EGF 也能更有效地诱导 ECFR 下调，这表明可能需要对 ErbB2 进行配体依赖性修饰来终止表达两种受体类型的细胞中的 EGFR 信号传导。这些发现表明，EGF 和 TGF α 诱导 ErbB2 酪氨酸磷酸化和异二聚化的能力不同，并提出了 ErbB2 部分通过损害 TGF α 依赖性 EGFR 下调来发挥其致癌作用的可能性。
The epidermal growth factor receptor (EGFR) is activated by a variety of ligands including EGF and transforming growth factor-alpha (TGF alpha), whereas no ligand for the homologous ErbB2 oncoprotein has yet been identified. Here we use both an ErbB2 phosphoantibody (aPY(1222)) and an activation-specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGF alpha, while EGFR is more potently activated by TGF alpha. Co-precipitation studies confirm that heterodimerization of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not TGF alpha. ECFR downregulation is also more efficiently induced by EGF, suggesting that ligand-dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types. These findings indicate that EGF and TGF alpha differ in their abilities to induce tyrosine phosphorylation and heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its oncogenic effect in part by impairing TGF alpha-dependent EGFR downregulation.