Regulation of mannose 6‐phosphate/insulin‐like growth factor II receptor distribution by activators and inhibitors of protein kinase C

Abstract

The tumor‐promotor phorbol dibutyrate (PDBt) increases the binding of a neoglycoprotein containing mannose 6‐phosphate (Man6P) and of insulin‐like growth factor II (IGF‐II) to the Man6P/IGF‐II receptor at the cell surface. This effect is dependent on time and concentration and is also seen with synthetic 1‐oleoyl‐2‐acetyl‐sn‐glycerol, but not with 4α‐phorbol, an inactive tumor‐promoter. The increase is due to a 3–4 fold increase in the number of cell‐surface, receptors, accompanied by a 1.6‐fold increase in ligand‐binding affinity. The internalization rate of the Man6P/IGF‐II receptor is not affected by PDBt, suggesting that the redistribution of these receptors to the cell surface is due to an accelerated externalization rate. The redistribution of Man6P/IGF‐II receptors did not impair the sorting of newly synthesized Man6P‐containing ligands while uptake of these ligands is 2–4‐fold increased. Inactivation or down regulation of protein kinase C decreased the binding of the Man6P‐containing neoglycoprotein to 65% of controls. Incubation of cells with Man6P, IGF‐I, IGF‐II or epidermal growth factor induces a rapid redistribution of Man6P/IGF‐II receptors to the plasma membrane [Braulke, T., Tippmer, S., Neher, E. & von Figura, K. (1989) EMBO J. 8, 681–686]. Incubation with PDBt prevented the effect of growth factors but not that of Man6P on receptor redistribution. Inactivation of protein kinase C did not affect the Man6P/IGF‐II receptor redistribution induced by Man6P and growth factors. These data suggest that Man6P, growth factors and activation of protein kinase C by phorbol esters and diacylglycerols modulate Man6P/IGF‐II receptor cell‐surface binding by at least two independent mechanisms, receptor redistribution as well as an increase of binding affinity, which might be involved in regulation of endocytosis of ligands. Copyright © 1990, Wiley Blackwell. All rights reserved