Sci. STKE, 27 April 2004
CAVEOLAR SIGNALING A Pump and a Signaling Receptor All in One
Evidence is mounting that the Na+,K+-ATPase is not just a regulator of ionic balance, but also a signal-transducing receptor for such ligands as ouabain, which were originally identified as inhibitors of the ion pump activity of Na+,K+-ATPase. Wang et al. revisited the question of whether Na+,K+-ATPase was located in caveolar membranes by using a detergent-free isolation method and found that Na+,K+-ATPase, caveolin-1, and the nonreceptor tyrosine kinase Src were abundant in these membrane microdomains from LLC-PK1 cells. Na+,K+-ATPase interacted with caveolin-1 in glutathione S-transferase pull-down experiments. Ouabain treatment of LLC-PK1 cells stimulated the association of Na+,K+-ATPase and caveolin-1 based on coimmunoprecipitation. In the response to ouabain, a Na+,K+-ATPase-caveolin-1-Src complex was detected by coimmunoprecipitation, and the tyrosine phosphorylation of caveolin-1, along with that of multiple other proteins, was stimulated in isolated caveolar membrane fractions. Exposure of cells to cholesterol-depleting agents promoted the redistribution of Na+,K+-ATPase and Src out of caveolin-1-positive membranes. Cholesterol depletion or depletion of caveolin-1 by RNA interference inhibited ouabain-stimulated increase in phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Thus, Na+,K+-ATPase appears to serve a dual role as an ion pump and a signaling receptor, with ouabain both inhibiting ion pumping activity and stimulating downstream signaling cascades mediated by protein kinases.
Citation: A Pump and a Signaling Receptor All in One. Sci. STKE 2004, tw149 (2004).
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