期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7255-7260
DOI：10.1073/pnas.1505917112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNetrin-1 has been considered a pro-oncogene due to its oncogenic activity. However, the mechanism by which netrin-1 modulates cancer progression is not well understood. Here, we show that netrin-1 promotes cancer cell proliferation and migration through up-regulating Yes-associated protein (YAP), a downstream target of the Hippo signaling pathway. Further studies suggest that, via uncoordinated-5 homolog B (UNC5B)/deleted in colorectal cancer receptors, netrin-1 enhances YAP stability via promoting phosphatase 1A-induced YAP dephosphorylation, leading to high levels of YAP activity. These results provide a mechanism of netrin-1 oncogenic activity and identify a cross-talk between the Hippo pathway and netrin signaling. 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.
