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.