Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.
Mol Cell. 2010 Feb 12;37(3):321-32. doi: 10.1016/j.molcel.2010.01.004.
EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3Delta4 that promote the localization of SRC-3Delta4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, overexpression of SRC-3Delta4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Delta4 as a missing adaptor between EGFR and its downstream signaling molecule FAK to coordinately regulate EGF-induced cell migration. Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme.
EGF 诱导 EGFR 和 FAK 之间的信号转导，而 FAK 是 EGF 诱导细胞迁移所必需的。然而，尚不清楚是什么因素介导了 EGFR 和 FAK 之间的相互作用，并导致了 EGF 诱导的 FAK 磷酸化。在这里，我们鉴定出 SRC-3Delta4，一种 SRC-3 癌基因的剪接异构体，作为一种信号接头，将 EGFR 和 FAK 连接起来，并促进 EGF 诱导的 FAK 和 c-Src 的磷酸化。我们鉴定出 SRC-3Delta4 中的三个 PAK1 介导的磷酸化，促进了 SRC-3Delta4 向质膜的定位，并介导了与 EGFR 和 FAK 的相互作用。重要的是，SRC-3Delta4 的过表达促进了 MDA-MB231 诱导的乳腺癌转移。我们的研究结果确定了磷酸化的 SRC-3Delta4 作为 EGFR 和其下游信号分子 FAK 之间缺失的接头，以协调调节 EGF 诱导的细胞迁移。我们的研究还表明，核受体共激活剂可以在细胞的外围发挥作用，直接介导酶的激活。
