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 gly coprotein (gp) 130 subunit for signal transduction. The specific receptor f or LIF, gp190, binds this cytokine with low affinity and is also required f or signal transduction. We have recently reported that glycosylated LIF pro duced by transfected Chinese hamster ovary cells also binds to a lectin-lik e 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., an d Godard, A. (1998) J. Biol. Chem. 273, 20886-20893). The present study sho ws that (i) mannose 6-phosphate-containing LIF is naturally produced by a n umber of normal and tumor cell lines; (ii) other cytokines in the interleuk in-6 family do not bind to Man-6-P/IGFII-R; and (iii) another unrelated cyt okine, macrophage-colony-stimulating factor, is also able to bind to Man-6- P/IG-FII-R in a mannose 6-phosphate-sensitive manner. No functional effects or signal transductions mediated by this lectin-like receptor were observe d in various biological assays after LIF binding, and mannose B-phosphate-c ontaining LIF was as active as non-glycosylated LIF. However, mannose 6-pho sphate-sensitive LIF binding resulted in rapid internalization and degradat ion of the cytokine on numerous cell lines, which suggests that Man-6-P/IGF II-R plays an important role in regulating the amounts of LIF available in vivo.