title: Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Qi
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84132;
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.affiliation: Department of Pathology and Lab Medicine, Harvard Medical School and Children's Hospital Boston, Boston, MA 02115;
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; kye@emory.edu.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D009414:Nerve Growth Factors / Q000502:physiology*; D000075388:Netrin-1; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000075388:Netrin-1
keywords: YAP; cancer progression; netrin-1