The Calcium Independent Mannose 6-Phosphate Receptor (CIMPR) is a receptor for multiple ligands, including Leukemia Inhibitory Factor (LIF), an interleukin(IL)-6 type cytokine, and insulin-like growth factor II (IGF-II). CIMPR targets newly synthesized ligands to lysosomes and induces internalization / degradation of secreted ligands. A natural soluble form of CIMPR (sCIMPR) neutralizes IGF-II mitogenic potency on hepatocytes and fibroblasts. Herein, we show that sCIMPR also inhibits LIF-driven proliferation of myeloid and lymphoid cell lines. Similar inhibition was observed with IL-6 and IL-11, two other IL-6-type cytokines which do not interact with CIMPR. Neutralizing anti-IGF-II antibodies inhibited IL-6-, IL-11- and LIF-driven cell proliferation to the same extent as sCIMPR, suggesting that neutralization of serum IGF-II by sCIMPR plays a major role in IL-6-type cytokines dependent cell proliferation. Confirming this notion, ERK1/2 and AKT, the kinases necessary for cell proliferation and survival, were activated by IGF-II alone or by the association of IL-6-type cytokines and IGF-II. IL-6-type cytokines alone (up to 10ng/ml) did not activate ERK1/2 nor AKT, but did activate STAT3, a transcription factor necessary for the G1 to S phase cell-cycle transition. Activation of ERK1/2 and AKT by IGF-II thus appears essential to sustain cellular expansion driven by IL-6-type cytokines.