Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Yes-associated protein (YAP) is a key regulator of organ size and cancer development, acting as a downstream effector of the Hippo pathway.
• The precise mechanisms by which extracellular stimuli regulate YAP in tumorigenesis are not fully understood.
• Netrin-1, a secreted protein with proto-oncogenic activity, has ill-defined downstream signaling pathways mediating its effects in cancer.

Purpose of the Study:

• To investigate how Netrin-1 regulates YAP expression and signaling in cancer.
• To elucidate the downstream molecular mechanisms by which Netrin-1 exerts its oncogenic effects.
• To identify potential therapeutic targets by understanding the Netrin-1/YAP axis in cancer progression.

Main Methods:

• Investigated the effect of Netrin-1 on YAP expression and localization using cancer cell models.
• Utilized receptor inactivation (deleted in colorectal cancer, UNC5B) and gene knockdown (MST1/2, Lats1/2) to dissect the Netrin-1 signaling pathway.
• Assessed the role of phosphatase 1A in Netrin-1-mediated YAP regulation.
• Measured cancer cell proliferation and migration in response to Netrin-1 signaling modulation.

Main Results:

• Netrin-1, through its receptors deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, increasing nuclear YAP levels.
• Inactivation of Netrin-1 or its receptors decreased YAP protein levels and inhibited Netrin-1-induced cancer cell progression.
• Knockdown of upstream Hippo pathway kinases (MST1/2, Lats1/2) did not block Netrin-1-induced YAP up-regulation.
• Netrin-1 stimulates phosphatase 1A, leading to YAP dephosphorylation, reduced ubiquitination, and decreased degradation, thereby enhancing YAP accumulation and signaling.

Conclusions:

• Netrin-1 promotes cancer cell proliferation and migration by up-regulating YAP signaling.
• The Netrin-1/receptor complex activates a pathway involving phosphatase 1A that stabilizes YAP.
• This study reveals a novel mechanism linking extracellular Netrin-1 signaling to nuclear YAP oncogenic activity, offering a potential therapeutic strategy.