Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability
Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability
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DOI：
10.1073/pnas.1505917112
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发表时间：
2015-06-09
影响因子：
11.1
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Qi, Qi;Li, Dean Y.;Ye, Keqiang
是相关蛋白（雅普）是一种转录共激活因子，是Hippo通路的主要下游效应子，在器官大小控制和肿瘤发生发展中起重要作用。然而，雅普在肿瘤发生中是如何受细胞外刺激调节的仍不完全清楚。Netrin-1是一种层粘连蛋白相关的分泌蛋白，在癌症中显示原癌活性。尽管如此，介导其致癌作用的下游信号还没有很好地定义。在这里，我们表明netrin-1通过其跨膜受体，在结直肠癌中缺失和不协调的5同源物，上调雅普表达，使细胞核中的雅普水平升高，并促进癌细胞增殖和迁移。失活netrin-1（在结直肠癌中缺失）或不协调的-5同源物B（UNC 5 B）降低雅普蛋白水平，通过netrin-1消除癌细胞进展，而敲低哺乳动物STE 20样蛋白激酶1/2（MST 1/2）或大肿瘤抑制激酶1/2（Lats 1/2），Hippo途径的两组上游核心激酶，在阻断netrin-1诱导的雅普上调方面没有效果。Netrin-1刺激磷酸酶1A使雅普去磷酸化，这导致泛素化和降解减少，增强雅普积累和信号传导。因此，我们的研究结果支持netrin-1通过雅普信号传导发挥致癌活性，提供了将细胞外信号与核雅普致癌基因偶联的机制。
Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development. However, how YAP is regulated by extracellular stimuli in tumorigenesis remains incompletely understood. Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers. Nonetheless, the downstream signaling mediating its oncogenic effects is not well defined. Here we show that netrin-1 via its transmembrane receptors, deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration. Inactivating netrin-1, deleted in colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein levels, abrogating cancer cell progression by netrin-1, whereas knockdown of mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway, has no effect in blocking netrin-1-induced up-regulation of YAP. Netrin-1 stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene.