The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion.

神经调节蛋白及其 ErbB/HER 受体在哺乳动物发育和组织稳态中发挥着重要作用。此外，它们功能的失调与癌症或精神分裂症等疾病的发病机制有关。这些情况刺激了对该配体-受体系统的生物学研究。在这里，我们展示了程序性细胞死亡蛋白 4 (PDCD4) 作为一种新型神经调节蛋白-ErbB 信号传导介质的鉴定。磷酸蛋白质组学分析确定 PDCD4 是一种蛋白质，其磷酸化在用神经调节蛋白处理的细胞中增加。诱变实验将 PDCD4 的丝氨酸 67 定义为在神经调节蛋白受体激活后磷酸化增加的位点。该位点的磷酸化促进了蛋白酶体对 PDCD4 的降解，这取决于 PDCD4 从细胞核到细胞质的退出。机制研究将 mTORC1 和 ERK1/2 定义为参与神经调节蛋白诱导的丝氨酸 67 磷酸化和 PDCD4 降解的途径。从功能上来说，PDCD4 调节神经调节蛋白的几个重要生物学功能，例如增殖、迁移或侵袭。