Abl interactor 1 binds to Sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases
Abl interactor 1 binds to Sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases
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DOI：
10.1128/mcb.20.20.7591-7601.2000
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发表时间：
2000-10-01
影响因子：
5.3
通讯作者：
Goff, SP
中科院分区：
文献类型：
--
作者：
Fan, PD;Goff, SP
最近的研究表明，Abl 相互作用蛋白 (Abi) 蛋白家族的成员对细胞生长和转化具有负调节作用。然而，迄今为止，尚未确定 Abi 家族在这些细胞过程中的具体作用。在这里，我们描述了过表达的 Abi-1 对生长因子和 v-Abl 激活的有丝分裂途径的抑制作用。我们已经确定鸟嘌呤核苷酸交换因子 Sos1 和 Sos2 作为 Abi-1 的新型结合伴侣。体内与 Sos 相互作用所需的结构域已被定位到 Abi-1 的氨基末端。 Abi-1 的过表达会抑制表皮生长因子 (EGF) 诱导的细胞外信号调节激酶 (Erks) 激活，但不影响 EGF 诱导的 c-Jun N 末端激酶或 Akt 激活。此外，Abi-1 的过度表达可阻断 v-Abl 诱导的 Erk 激活。在这两种情况下，最大的抑制效果需要 Abi-1 中完整的氨基末端 Sos 结合结构域。最后，我们证明成纤维细胞中内源性 Abi-1 的酪氨酸磷酸化是由 v-Abl 和血清刺激诱导的，进一步表明 Abi-1 在 v-Abl 和生长因子启动的信号转导中的作用。综上所述，这些发现表明，过度表达的 Abi 蛋白通过特异性靶向 Erk 通路来负向调节细胞生长和转化。
Recent studies have suggested that members of the Abl interactor (Abi) protein family negatively regulate cell growth and transformation. To date, however, no specific role in these cellular processes has been identified for the Abi family. Here we describe the inhibition by overexpressed Abi-1 of a mitogenic pathway activated by both growth factors and v-Abl. We have identified the guanine nucleotide exchange factors Sos1 and Sos2 as novel binding partners of Abi-1. A domain that is required for interaction with Sos in vivo has been mapped to the amino terminus of Abi-1. Overexpression of Abi-1 inhibits epidermal growth factor (EGF)-induced activation of extracellular signal-regulated kinases (Erks) but does not affect EGF-induced activation of c-Jun N-terminal kinase or Akt. In addition, overexpression of Abi-1 blocks Erk activation induced by v-Abl. In both cases, the maximal inhibitory effect requires an intact amino-terminal Sos-binding domain in Abi-1. Finally, we demonstrate that tyrosine phosphorylation of endogenous Abi-1 in fibroblasts is induced by both v-Abl and serum stimulation, further suggesting a role for Abi-1 in signal transduction initiated by v-Abl and growth factors. Taken together, these findings suggest that overexpressed Abi proteins negatively regulate cell growth and transformation by specifically targeting the Erk pathway.