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.netrin-1 | YAP | cancer progression

Neogenin-YAP signaling in neocortical astrocytic differentiation

“…49 Our studies suggest that neogenin/RhoA/ YAP/Smad1 signaling plays a critical role in BMP2-induced astrocyte differentiation of NSCs. Although netrin-1 via DCC receptor up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration, 50 our results showed that netrin-1 did not regulate YAP level in WT or neogenin mutant astrocytes. Further investigation is necessary to illustrate whether neogenin/RhoA/YAP/Smad1 signaling pathway is involved in BMPs-induced differentiation of GICs, which may reveal novel therapeutic targets for astroglioma.…”

Dependence Receptors and Cancer: Addiction to Trophic Ligands

“…As a consequence, combining conventional drugs and netrin-1 interference increases tumor cell death in vitro and potentiates tumor growth inhibiting effect in vivo, thus suggesting that, even when tumors do not express high levels of netrin-1, a combination of conventional drugs plus drugs inhibiting netrin-1-receptors interaction could amplify the chemotherapy-induced response. As discussed above, netrin-1 may not only have a pro-oncogenic effect by blocking the death induced by DCC or UNC5H, it may also activate "protumorigenic" pathways, as recently shown by the implication of the YAP pathway (38), thus further strengthening the rationale for moving netrin-1 interference into the clinic. A humanized monoclonal antibody disrupting netrin-1-receptors interaction is under preclinical development, with a clinical phase I scheduled for early 2016.…”

An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

“…Because PP1A may dephosphorylate YAP primarily on S397 (Qi et al, 2015), we tested whether PP1A binding to YAP was diminished upon Cdc42 deletion. To that end, we performed co-immunoprecipitation of YAP and PP1A and found a significant reduction in pulled-down PP1A (but not PP2A, data not shown) in Cdc42 cKO laCL lysates (Figure 6J).…”