Figure 3.

The NaK functions as a receptor for cardiotonic steroid inhibitors. In addition to pumping ions (Na⁺ and K⁺) across the plasma membrane using ATP as the driving force (A), the sodium pump in caveolae is engaged in the assembly of multiple protein complexes that transmit signals to different intracellular compartments (B). (A) For every three Na⁺ ions pumped out of the cell, two K⁺ ions are pumped in. The partial inhibition of the sodium pump by the cardenolide ouabain causes a modest change in [Na⁺]_i and [K⁺]_i, and a significant change in [Ca²⁺]_i through the Na⁺/Ca²⁺-exchanger. (B) The NaK signalosome closely interacts with major components of gliomagenesis: EGFR, caveolin-1, PI3K, Src, and Ras. On ouabain binding, the NaK α₁ subunit in caveolae associates with several proteins, such as caveolin-1 through two caveolin-binding motifs and Src through multiple domains. Activated Src secondarily trans-activates EGFR which in turn recruits the adapter protein Shc to relay signals to the Ras-Raf-MAPKs cascade. In contrast, UNBS1450 at 10 nM, a concentration at which it demonstrates potent antiproliferative and antimigratory activity, does not elicit increases in [Ca²⁺]_i or [Na⁺]_i in cells but the compound decreases ([ATP]_i). Grb2 indicates growth factor receptor-bound protein 2; MEK, MAPK-ERK-activating kinase; PKC, protein kinase C; PLC, phospholipase C; Ros, reactive oxygen species; Shc, src homology collagen-like protein; Sos, son of sevenless.