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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...

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Autores principales: He, Kunyan, Jang, Sung-Wuk, Joshi, Jayashree, Yoo, Min-Heui, Ye, Keqiang
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2011
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
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author He, Kunyan
Jang, Sung-Wuk
Joshi, Jayashree
Yoo, Min-Heui
Ye, Keqiang
author_facet He, Kunyan
Jang, Sung-Wuk
Joshi, Jayashree
Yoo, Min-Heui
Ye, Keqiang
author_sort He, Kunyan
collection PubMed
description 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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spelling pubmed-31034092011-08-16 Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner He, Kunyan Jang, Sung-Wuk Joshi, Jayashree Yoo, Min-Heui Ye, Keqiang Mol Biol Cell Articles 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. The American Society for Cell Biology 2011-06-01 /pmc/articles/PMC3103409/ /pubmed/21460185 http://dx.doi.org/10.1091/mbc.E10-11-0923 Text en © 2011 He et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB”, “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
He, Kunyan
Jang, Sung-Wuk
Joshi, Jayashree
Yoo, Min-Heui
Ye, Keqiang
Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title_full Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title_fullStr Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title_full_unstemmed Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title_short Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
title_sort akt-phosphorylated pike-a inhibits unc5b-induced apoptosis in cancer cell lines in a p53-dependent manner
topic Articles
url 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
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