The Na/K‐ATPase/Caveolin‐1 Interaction Regulates Cell Growth Via A Cholesterol‐Dependent Mechanism

Abstract

The Na/K‐ATPase α1 subunit contains a highly conserved caveolin‐1 binding motif (CBM). We have previously shown that the interaction between the α1 CBM and caveolin‐1 regulates the formation of caveolae, and intracellular trafficking and distribution of cholesterol. Here we demonstrate an important role of this interaction in control of cell growth. First, we find that knockdown of either Na/K‐ATPase or caveolin‐1 inhibits cell proliferation and that this inhibition is greatly enhanced by modest depletion of cellular cholesterol. Second, the expression of wild‐type α1, but not the CBM mutant, is capable of restoring normal growth in LLC‐PK1 cells. Finally, we find that the expression of N‐terminus of the α1 subunit inhibits the interaction between the Na/K‐ATPase and caveolin‐1. Consequently, it alters normal trafficking of caveolin‐1 and cholesterol, and inhibits cell growth. Taken together, our new findings demonstrate that the highly conserved caveolin binding motif of the Na/K‐ATPase plays an important role in regulation of cell growth by affecting the trafficking and distribution of caveolin‐1 and cholesterol (supported by NIH grants HL36573 and GM78565).