Summary: On the importance and mechanism of amplification o...[Cell Mol Biol (Noisy-le-grand). 2006] - PubMed Result
Cell Mol Biol (Noisy-le-grand). 2006 Dec 30;52(8):28-30. Links
On the importance and mechanism of amplification of digitalis
signal through Na+/K+-ATPase.
Liu L, Askari A.
Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences Medical University of
Ohio, Toledo, Ohio 43614-5804, USA.
Therapeutic concentrations of digitalis drugs inhibit the proliferation of breast cancer cells by inducing
the interaction of Na+/K+-ATPase with Src/EGFR, activation of ERK1/2, and the resulting upregulation of cell
cycle inhibitor p21Cip1. Quantitative comparison of ouabain dose-response curves for growth arrest and
pump inhibition shows that ratio of Ki (pump)/Ki (proliferation) = 7.2. Such large gains in sensitivity
are characteristic of several signal transducing pathways of other receptors. Making the reasonable
assumption that Na+/K+-ATPase is the only receptor for ouabain, the large amplification factor clearly shows
that occupation of a small fraction of pumping Na+/K+-ATPase by digitalis drugs, or endogenous digitalis-
like factors, is sufficient to cause near complete inhibition of cell growth. The likely causes of large
amplification factor in the signaling function of Na+/K+-ATPase include (a) interactions among the protomers of
Na+/K+-ATPase in the membrane; and (b) induced clustering of Na+/K+-ATPase oligomers with
neighboring proteins. The upstream location of both mechanisms suggests that similar amplifications also occur
in other cell types with different digitalis downstream effects; e.g., stimulation of proliferation or hypertrophy.
PMID: 17535733 [PubMed - indexed for MEDLINE]