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Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
UNC5B acts as a tumor suppressor, and it induces apoptosis in the absence of its cognate ligand netrins. UNC5B is a direct transcriptional target of p53 upon UV stimulation. Here we show that Akt phosphorylates PIKE-A and regulates its association with UNC5B and inhibits UNC5B-provoked apoptosis in...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103409/ https://www.ncbi.nlm.nih.gov/pubmed/21460185 http://dx.doi.org/10.1091/mbc.E10-11-0923 |
Sumario: | UNC5B acts as a tumor suppressor, and it induces apoptosis in the absence of its cognate ligand netrins. UNC5B is a direct transcriptional target of p53 upon UV stimulation. Here we show that Akt phosphorylates PIKE-A and regulates its association with UNC5B and inhibits UNC5B-provoked apoptosis in a p53-dependent manner. PIKE-A GTPase binds active Akt and stimulates its kinase activity in a guanine-nucleotide–dependent way. Akt feeds back and phosphorylates PIKE-A on Ser-472 and subsequently enhances its stimulatory effect on Akt kinase activity. Akt activity is significantly reduced in PIKE −/− Mouse Embryonic Fibroblast (MEF) cells as compared to wild-type cells. PIKE-A directly interacts with UNC5B, which is regulated by netrin-1–activated Akt. Overexpression of PIKE-A diminishes UNC5B expression through down-regulation of p53. Knocking down PIKE-A stabilizes p53, increases UNC5B, and escalates UV-triggered apoptosis. Depletion of Akt abrogates PIKE-A's inhibitory effect on both p53 and UNC5B. Hence our findings support the notion that Akt-phosphorylated PIKE-A inhibits UNC5B-elicited apoptosis and reduces its expression level through inactivation of p53. |
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