{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T16:59:24Z","timestamp":1759683564773},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,10,12]],"date-time":"2005-10-12T00:00:00Z","timestamp":1129075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2006,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In this study, we demonstrated that the specific inhibitors of the Na+\/K+\/Cl\u2212 cotransporter (NKCC1), bumetanide and furosemide, inhibited extracellular regulated kinase (ERK) phosphorylation in Balb\/c 3T3 fibroblasts, stimulated with a variety of mitogens. In addition to fibroblast growth factor (FGF) shown before, the various mitogens tested in the present study (endothelial growth factor (EGF), platelet\u2010derived growth factor (PDGF), insulin, thrombin, and the phorbol ester, 12\u2010<jats:italic>O<\/jats:italic>\u2010tetradecanoyl\u2010phorbol\u201013\u2010acetate (TPA)). Enter, the Ras\/Raf\/MEK\/ERK cascade via different growth factors receptors and through one of the two main routes. The results of the present study provide evidence that have led us to conclude that the target protein which is controlled by the Na+\/K+\/Cl\u2212 cotransporter, is downstream of tyrosine kinase receptors, as well as of the G\u2010protein\u2010coupled receptor (GPCR)<jats:italic>.<\/jats:italic> Several additional lines of evidence supported the above conclusion: (i) furosemide inhibits phosphorylation of MAPK kinase (MEK) induced by receptor tyrosine kinase (RTK) ligands, such as PDGF, FGF, and EGF. (ii) Furosemide also inhibited ERK phosphorylation, induced by thrombin, a GPCR. (iii) Furosemide inhibited MEK and ERK phosphorylation even when ERK phosphorylation was induced by direct activation of protein kinase C (PKC) by TPA, which bypasses early steps of the mitogenic cascade. In addition, we found that furosemide did not affect PKC phosphorylation induced directly by TPA. Taken together, the results of the present study indicate that the signal transduction protein, controlled by the Na+\/K+\/Cl\u2212 cotransporter, must be downstream of the PKC, and at\/or upstream to MEK in the Ras\/Raf\/MEK\/ERK cascade. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.20506","type":"journal-article","created":{"date-parts":[[2005,10,12]],"date-time":"2005-10-12T22:16:54Z","timestamp":1129155414000},"page":"578-585","source":"Crossref","is-referenced-by-count":27,"title":["Na+\/K+\/Cl\u2212 cotransporter activates MAP\u2010kinase cascade downstream to protein kinase C, and upstream to 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