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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21765932/pdf/?tool=EBI |
| _version_ | 1828954218863525888 |
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| 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 |
| collection | DOAJ |
| 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. |
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| format | Article |
| id | doaj.art-22fd83c4eac744e897a1462c4a18b6d9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T07:25:44Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-22fd83c4eac744e897a1462c4a18b6d92022-12-21T23:11:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0167e2199110.1371/journal.pone.0021991A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells.Lihua LiangOwen M WoodwardZhaohui ChenRobert CotterWilliam B GugginoCa(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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21765932/pdf/?tool=EBI |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21765932/pdf/?tool=EBI |
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