The Journal of Cell Biology, Vol 106, 395-401, Copyright © 1988 by The Rockefeller University Press
Role of extracellular electrolytes in the activation of ribosomal protein S6 kinase by epidermal growth factor, insulin-like growth factor 1, and insulin in ZR-75-1 cells
I Novak-Hofer, W Kung and U Eppenberger
Department of Research, University Clinic Medical School, Basel, Switzerland.
Activation of ribosomal protein S6 kinase by epidermal growth factor (EGF),
insulin, and insulin-like growth factor 1 (IGF1) was studied in the human
mammary tumor cell line ZR-75-1 in isotonic buffers. In contrast to growth
factor-dependent S6 phosphorylation which is strongly dependent on
extracellular pH (Chambard, J. C., and J. Pouyssegur. 1986. Exp. Cell Res.
164:282-294.) preincubation of cells in buffers with different pH values
ranging from 7.5 to 6.5 had no effect on basal or EGF-stimulated S6 kinase
activity. Replacement of extracellular Na+ with choline or replacement of
extracellular Ca++ with EGTA also did not inhibit stimulation of S6 kinase
by EGF. When intracellular Ca++ was buffered with the permeable Ca++
chelator quin2, EGF stimulation was reduced 50%. A similar inhibition of
the EGF response was observed when cells were incubated in buffers with
high K+ concentrations or in the presence of the K+ ionophore valinomycin.
Insulin and IGF1 stimulation of S6 kinase were also inhibited by high K+
concentrations and by buffering intracellular Ca++. In contrast to the
responses to EGF, insulin- and IGF1-activation of S6 kinase was enhanced
when glucose was present and depended on the presence of bicarbonate in the
medium. The results indicate that ionic signals generated by growth factors
and insulin, such as increases in intracellular pH or Na+, do not seem to
be involved in the activation of S6 kinase. However, effects of growth
factors or insulin on membrane potential and/or K+ fluxes and
redistribution of intracellular Ca++ may play a role in the activation
process. Furthermore, the mechanism of insulin activation of S6 kinase is
distinct from the growth factors by its dependency on extracellular
bicarbonate.
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