Abstract
Phorbol esters are potent tumour-promoting agents that exert pleiotropic effects on cells1–3. Among these are the control of growth4, stimulation of release of stored bioactive constituents5–8 and regulation of growth-factor surface receptors9–13. Phorbol esters bind to and activate protein kinase C, leading to the phosphorylation of specific protein substrates presumed to be necessary for eliciting the full response6,8–12,14,15. Strong evidence exists that specific binding of tumour promoter occurs at the membrane level in intact cells, resulting in activation of protein kinase C16,17. Recent evidence concerning the release of bioactive constituents from platelets5,8,14,18,19 and neutrophils5,6 has linked agonist-induced protein kinase C activation and Ca2+ mobilization in a synergistic mechanism8,20,21. Here we present a novel model of synergism between Ca2+ and phorbol esters that leads to transferrin receptor phosphorylation and down-regulation in HL-60 human leukaemic cells. Raising intracellular Ca2+, although ineffective by itself, increases the potency and rate of action of phorbol ester for activating protein kinase C and mediating transferrin receptor phosphorylation and down-regulation. We propose a molecular model in which increased intracellular Ca2+ recruits protein kinase C to the plasma membrane, thus ‘priming’ the system for activation by phorbol ester.
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May, W., Sahyoun, N., Wolf, M. et al. Role of intracellular calcium mobilization in the regulation of protein kinase C-mediated membrane processes. Nature 317, 549–551 (1985). https://doi.org/10.1038/317549a0
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DOI: https://doi.org/10.1038/317549a0
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