SURAMIN MODULATES CELLULAR-LEVELS OF HEPATOCYTE GROWTH-FACTOR RECEPTOR BY INDUCING SHEDDING OF A SOLUBLE FORM

Several growth factor receptors undergo shedding from the cell surface as a result of limited proteolysis via mechanisms that are at present poorly understood. By Western blotting of the conditioned media and c ell lysates of several cell lines expressing the hepatocyte growth fac tor receptor, we found that suramin, a pharmacological agent that inhi bits the activity of many growth factors, was able to induce shedding of this receptor. increased levels of soluble hepatocyte growth factor receptor were observed in the conditioned media of GTL-16, a cell lin e over-expressing the receptor, as early as ten minutes after initial exposure to the agent, and incubation of this line with 300 mu M suram in caused a 50% reduction in cell-associated levels of receptor after 6 hours. Although protein kinase C activation by treatment of cells wi th phorbol eaters has previously been found to stimulate shedding of t he hepatocyte growth factor receptor, this hitherto undescribed activi ty of suramin was not affected by protein kinase C inhibitors. Since s hedding represents a possible means of downmodulation of receptor acti vity, suramin may inhibit the hepatocyte growth factor ligand/receptor system, not only by abrogation of hepatocyte growth factor binding to intact receptor, but also by induction of receptor shedding.