The adherens junction protein afadin is an AKT substrate that regulates breast cancer cell migration.
The adherens junction protein afadin is an AKT substrate that regulates breast cancer cell migration.
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DOI：
10.1158/1541-7786.mcr-13-0398
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Toker A
中科院分区：
文献类型：
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作者：
Elloul S;Kedrin D;Knoblauch NW;Beck AH;Toker A
PI3-K和Akt信号通路调节所有促进人类癌症进展的表型，包括乳腺癌。AKT通过磷酸化许多底物来介导信号传递，这些底物与细胞的生长、存活、代谢重新编程以及迁移和侵袭等反应密切相关。在这里，我们发现了一种新的Akt底物，粘着连接蛋白Afadin，它在Ser1718被Akt磷酸化。我们证明在生理性的IGF-1信号和致癌的PI3-K和Akt的条件下，Afadin被所有Akt亚型磷酸化，并且这种磷酸化导致Afadin从粘着连接到细胞核的重新定位。Afadin的磷酸化还导致依赖Ser1718磷酸化的乳腺癌细胞迁移显着增加。我们还观察到乳腺癌组织中的核定位，表明PI3-K和Akt通路对Afadin的调节具有病理生理意义。粘着蛋白Afadin被PI3-K途径下游的Akt磷酸化，导致Afadin的重新分布，并控制癌细胞的迁移。
The PI 3-K and Akt signaling pathway regulates all phenotypes that contribute to progression of human cancers, including breast cancer. Akt mediates signal relay by phosphorylating numerous substrates, which are causally implicated in responses such as cell growth, survival, metabolic reprograming and migration and invasion. Here we identify a new Akt substrate, the adherens junction protein Afadin, that is phosphorylated by Akt at Ser1718. We show that under conditions of physiological IGF-1 signaling and oncogenic PI 3-K and Akt, Afadin is phosphorylated by all Akt isoforms, and that this phosphorylation elicits a relocalization of Afadin from adherens junctions to the nucleus. Phosphorylation of Afadin also results in a marked increase in breast cancer cell migration that is dependent on Ser1718 phosphorylation. We also observe nuclear localization in breast cancer tissues, indicating that regulation of Afadin by the PI 3-K and Akt pathway has pathophysiological significance. Phosphorylation of the adhesion protein Afadin by Akt downstream of the PI 3-K pathway, leads to re-distribution of Afadin and controls cancer cell migration.