A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.

Ca(2+) activated Cl(-) channels (CaCC) are up-regulated in cystic fibrosis (CF) airway surface epithelia. The presence and functional properties of CaCC make it a possible therapeutic target to compensate for the deficiency of Cl(-) secretion in CF epithelia. CaCC is activated by an increase in cyto...

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Autores principales:	Lihua Liang, Owen M Woodward, Zhaohui Chen, Robert Cotter, William B Guggino
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/22fd83c4eac744e897a1462c4a18b6d9
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spelling	oai:doaj.org-article:22fd83c4eac744e897a1462c4a18b6d92021-11-18T06:50:21ZA novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.1932-620310.1371/journal.pone.0021991https://doaj.org/article/22fd83c4eac744e897a1462c4a18b6d92011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21765932/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Ca(2+) activated Cl(-) channels (CaCC) are up-regulated in cystic fibrosis (CF) airway surface epithelia. The presence and functional properties of CaCC make it a possible therapeutic target to compensate for the deficiency of Cl(-) secretion in CF epithelia. CaCC is activated by an increase in cytosolic Ca(2+), which not only activates epithelial CaCCs, but also inhibits epithelial Na(+) hyperabsorption, which may also be beneficial in CF. Our previous study has shown that spiperone, a known antipsychotic drug, activates CaCCs and stimulates Cl(-) secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro, and in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) knockout mice in vivo. Spiperone activates CaCC not by acting in its well-known role as an antagonist of either 5-HT2 or D2 receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Moreover, spiperone independently activates CFTR through a novel mechanism. Herein, we performed a mass spectrometry analysis and identified the signaling molecule that mediates the spiperone effect in activating chloride secretion through CaCC and CFTR. Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor protein tyrosine kinase, which belongs to the focal adhesion kinase family. The inhibition of PYK2 notably reduced the ability of spiperone to increase intracellular Ca(2+) and Cl(-) secretion. In conclusion, we have identified the tyrosine kinase, PYK2, as the modulator, which plays a crucial role in the activation of CaCC and CFTR by spiperone. The identification of this novel role of PYK2 reveals a new signaling pathway in human airway epithelial cells.Lihua LiangOwen M WoodwardZhaohui ChenRobert CotterWilliam B GugginoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e21991 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lihua Liang Owen M Woodward Zhaohui Chen Robert Cotter William B Guggino A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
description	Ca(2+) activated Cl(-) channels (CaCC) are up-regulated in cystic fibrosis (CF) airway surface epithelia. The presence and functional properties of CaCC make it a possible therapeutic target to compensate for the deficiency of Cl(-) secretion in CF epithelia. CaCC is activated by an increase in cytosolic Ca(2+), which not only activates epithelial CaCCs, but also inhibits epithelial Na(+) hyperabsorption, which may also be beneficial in CF. Our previous study has shown that spiperone, a known antipsychotic drug, activates CaCCs and stimulates Cl(-) secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro, and in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) knockout mice in vivo. Spiperone activates CaCC not by acting in its well-known role as an antagonist of either 5-HT2 or D2 receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Moreover, spiperone independently activates CFTR through a novel mechanism. Herein, we performed a mass spectrometry analysis and identified the signaling molecule that mediates the spiperone effect in activating chloride secretion through CaCC and CFTR. Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor protein tyrosine kinase, which belongs to the focal adhesion kinase family. The inhibition of PYK2 notably reduced the ability of spiperone to increase intracellular Ca(2+) and Cl(-) secretion. In conclusion, we have identified the tyrosine kinase, PYK2, as the modulator, which plays a crucial role in the activation of CaCC and CFTR by spiperone. The identification of this novel role of PYK2 reveals a new signaling pathway in human airway epithelial cells.
format	article
author	Lihua Liang Owen M Woodward Zhaohui Chen Robert Cotter William B Guggino
author_facet	Lihua Liang Owen M Woodward Zhaohui Chen Robert Cotter William B Guggino
author_sort	Lihua Liang
title	A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
title_short	A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
title_full	A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
title_fullStr	A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
title_full_unstemmed	A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
title_sort	novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/22fd83c4eac744e897a1462c4a18b6d9
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A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.

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