MECHANISM AND SIGNIFICANCE

BIOLOGICAL OF THE Ha-ras-INDUCED ACTIVATION OF THE Na+/H+-ANTIPORTER K. MALY, B. HOCHLEITNER, F. OBERALL, H. LOFERER, H. OBERHUBER, W. DOPPLER and H. GRUNICKE Institute for Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria

INTRODUCTION

Stimulation of the Na+/H+-antiporter and the resulting cytosolic alkalinization have been observed under the influence of many growth factors and mitogens and are considered as either essential or at least permissive for the proliferative response (for reviews see Refs 1 and 2). In previous publications we have demonstrated that expression of a transforming Ha-ras oncogene, not, however, of the corresponding proto-oncogene, leads to a growth factor-independent activation of the Na+/H+-antiporter (3, 4). Similar results have been obtained by others following microinjection of p21 ras (5). These findings support the supposition of a constitutive activation of a mitogenic signal transduction pathway by the Ha-ras oncogene. The mechanism by which Ha-ras stimulates the antiporter has remained unclear. In a variety of systems the activation of the Na+/H+-antiporter is mediated by the phospholipid- and Ca2+-dependent protein kinase (protein kinase C, EC 2.7.1.37) (1, 2). Evidence for an activation of protein kinase C by Ha-ras has been presented (4, 6-10). In view of these data it seemed most likely that Ha-ras affects the antiporter via protein kinase C. The data presented here demonstrate, however, that the activation of the antiporter by Ha-ras occurs by a protein kinase C-independent mechanism. The biological significance of the cytosolic alkalinization which is observed as a result of the mitogen or ras-induced activation of the Na+/H+-antiporter is still obscure. The data presented here indicate that the mobilization of intracellular calcium by serum growth factors or bombesin is a pH-dependent process and that the activation of the antiporter facilitates the release of Ca 2+ from intracellular stores in quiescent cells with apH

H(+)-antiporter.

Expression of the transforming Ha-ras oncogene in MMTV-LTR transfected NIH 3T3 cells leads to a growth factor independent activation of the Na+/H(+)-a...
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