Regulation of mannose 6-phosphate/insulin-like growth factor II receptor distribution by activators and inhibitors of protein kinase C.
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 4 alpha-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.
Braulke
T
T
Georg-August-Universität Göttingen, Biochemie II, Federal Republic of Germany.
Tippmer
S
S
Chao
H J
HJ
von Figura
K
K
D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006600:Hexosephosphates / Q000378:metabolism*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008360:Mannosephosphates / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D017451:Receptors, Somatomedin; D013002:Somatomedins / Q000378:metabolism*
D004075:Diglycerides; D006600:Hexosephosphates; D008360:Mannosephosphates; D010703:Phorbol Esters; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D013002:Somatomedins; D007335:Insulin-Like Growth Factor II; D011493:Protein Kinase C