The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor

Secreted proteins and their cognate receptors are implicated in a myriad of activities that regulate cell proliferation, differentiation, and development. CREG, a cellular repressor of E1A-stimulated genes, is a secreted glycoprotein that antagonizes cellular transformation by E1A and Ras. We have previously shown that CREG expression is induced very early during differentiation of pluripotent cells and, even in the absence of other inducers, CREG promotes neuronal differentiation of human teratocarcinoma NTERA-2 cells. Here we show that ectopic expression of CREG in NTERA-2 cells results in a delay of the G1/S phase transition of the cell cycle and growth inhibition. We show that CREG binds directly to the mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) dependent on CREG glycosylation. The M6P/IGF2R is a tumor suppressor that functions to control cell growth through interactions with multiple ligands. By analysing CREG activity in cells lacking M6P/IGF2R expression, we show that this receptor is required for CREG-induced growth inhibition. These studies reveal that CREG inhibits cell growth dependent on the M6P/IGF2R and suggest that interactions between CREG and a well-characterized tumor suppressor may contribute to regulation of proliferation and differentiation in multiple lineages.