1. Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability
- Author
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Qi, Qi, Li, Dean Y, Luo, Hongbo R, Guan, Kun-Liang, and Ye, Keqiang
- Subjects
Cancer ,Digestive Diseases ,Colo-Rectal Cancer ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Adaptor Proteins ,Signal Transducing ,Carcinogenesis ,Cell Line ,Tumor ,Cell Nucleus ,Cell Proliferation ,Humans ,Nerve Growth Factors ,Netrin-1 ,Phosphoproteins ,Phosphorylation ,Protein Stability ,Signal Transduction ,Transcription Factors ,Tumor Suppressor Proteins ,Up-Regulation ,YAP-Signaling Proteins ,YAP ,cancer progression ,netrin-1 - Abstract
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.
- Published
- 2015