Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells

Cellular phenotype is determined not only by genetic transcription but also by subsequent translation of mRNA into protein. Extracellular signals trig ger intracellular pathways that distinctly activate translation. The 70/85- kDa S6 kinase (pp70(S6k)) is a central enzyme in the signal-dependent contr ol of translation, but its regulation in endothelial cells is largely unkno wn. Here we show that fluid flow tin the absence of an exogenous mitogen) a s well as humoral agonists activate endothelial pp70(S6k). Rapamycin, an in hibitor of the mammalian target of rapamycin (mTOR), and wortmannin, a phos phatidylinositol 3-kinase inhibitor, blocked flow-induced pp70(S6k) activat ion; FK-506, a rapamycin analog with minimal mTOR inhibitory activity, and PD-98059, an inhibitor of the flow-sensitive mitogen-activated protein kina se pathway, had no effect. Synthesis of Bcl-3, a protein whose translation is controlled by an mTOR-dependent pathway, was induced by flow and inhibit ed by rapamycin and wortmannin. Transcriptional blockade did not abolish th e flow-induced upregulation of Bcl-3. Fluid forces may therefore modify end othelial phenotype by specifically regulating translation of certain mRNA t ranscripts into protein.