Mannose 6-Phosphate/Insulin-like growth factor II receptor mediates internalization and degradation of leukemia inhibitory factor but not signal transduction.
Leukemia inhibitory factor (LIF) is a multifunctional cytokine belonging to the interleukin-6 subfamily of helical cytokines, all of which use the glycoprotein (gp) 130 subunit for signal transduction. The specific receptor for LIF, gp190, binds this cytokine with low affinity and is also required for signal transduction. We have recently reported that glycosylated LIF produced by transfected Chinese hamster ovary cells also binds to a lectin-like receptor, mannose 6-phosphate/insulin-like growth factor II receptor (Man-6-P/IGFII-R) (Blanchard, F., Raher, S., Duplomb, L., Vusio, P., Pitard, V., Taupin, J. L., Moreau, J. F., Hoflack, B., Minvielle, S., Jacques, Y., and Godard, A. (1998) J. Biol. Chem. 273, 20886-20893). The present study shows that (i) mannose 6-phosphate-containing LIF is naturally produced by a number of normal and tumor cell lines; (ii) other cytokines in the interleukin-6 family do not bind to Man-6-P/IGFII-R; and (iii) another unrelated cytokine, macrophage-colony-stimulating factor, is also able to bind to Man-6-P/IGFII-R in a mannose 6-phosphate-sensitive manner. No functional effects or signal transductions mediated by this lectin-like receptor were observed in various biological assays after LIF binding, and mannose 6-phosphate-containing LIF was as active as non-glycosylated LIF. However, mannose 6-phosphate-sensitive LIF binding resulted in rapid internalization and degradation of the cytokine on numerous cell lines, which suggests that Man-6-P/IGFII-R plays an important role in regulating the amounts of LIF available in vivo.
Blanchard
F
F
Groupe de Recherche Cytokines/Récepteurs/Transduction, Unité INSERM 463, Institut de Biologie, 9 Quai Moncousu, 44035 Nantes Cedex 01, France. fblan@inserm.nantes.fr
Duplomb
L
L
Raher
S
S
Vusio
P
P
Hoflack
B
B
Jacques
Y
Y
Godard
A
A
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D006031:Glycosylation; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008360:Mannosephosphates / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D016173:Macrophage Colony-Stimulating Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium