Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.

The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknow...

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Autores principales:	Daniel Thomas, Jason A Powell, Benjamin D Green, Emma F Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C W Zannettino, Stuart M Pitson, Timothy P Hughes, Angel F Lopez, Peter R Shepherd, Andrew H Wei, Paul G Ekert, Mark A Guthridge
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6f994d55521847ca88fc793137e8fae9
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spelling	oai:doaj.org-article:6f994d55521847ca88fc793137e8fae92021-11-18T05:37:12ZProtein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.1544-91731545-788510.1371/journal.pbio.1001515https://doaj.org/article/6f994d55521847ca88fc793137e8fae92013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23526884/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel ThomasJason A PowellBenjamin D GreenEmma F BarryYuefang MaJoanna WoodcockStephen FitterAndrew C W ZannettinoStuart M PitsonTimothy P HughesAngel F LopezPeter R ShepherdAndrew H WeiPaul G EkertMark A GuthridgePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 3, p e1001515 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Daniel Thomas Jason A Powell Benjamin D Green Emma F Barry Yuefang Ma Joanna Woodcock Stephen Fitter Andrew C W Zannettino Stuart M Pitson Timothy P Hughes Angel F Lopez Peter R Shepherd Andrew H Wei Paul G Ekert Mark A Guthridge Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
description	The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.
format	article
author	Daniel Thomas Jason A Powell Benjamin D Green Emma F Barry Yuefang Ma Joanna Woodcock Stephen Fitter Andrew C W Zannettino Stuart M Pitson Timothy P Hughes Angel F Lopez Peter R Shepherd Andrew H Wei Paul G Ekert Mark A Guthridge
author_facet	Daniel Thomas Jason A Powell Benjamin D Green Emma F Barry Yuefang Ma Joanna Woodcock Stephen Fitter Andrew C W Zannettino Stuart M Pitson Timothy P Hughes Angel F Lopez Peter R Shepherd Andrew H Wei Paul G Ekert Mark A Guthridge
author_sort	Daniel Thomas
title	Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
title_short	Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
title_full	Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
title_fullStr	Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
title_full_unstemmed	Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
title_sort	protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/6f994d55521847ca88fc793137e8fae9
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Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.

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