Endocytosis of insulin-like growth factor II by a mini-receptor based on repeat 11 of the mannose 6-phosphate/insulin-like growth factor II receptor

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF-II receptor) plays an important role in controlling the extracellular level of the insulin-like growth factor II (IGF-II) by mediating its binding at the cell surface and delivery to lysosomes. Loss of the receptor is associated with an accumulation of IGF-II, which can cause perinatal lethality if it is systemic, or local proliferation and tumorgenesis if it is spatially res tricted. The extracytoplasmic domain of the receptor consists of 15 homolog ous repeats, of which repeat 11 carries the IGF-II-binding site of the mult ifunctional receptor. To investigate whether repeat 11 is sufficient to med iate binding and internalization of IGF-II, a construct consisting of repea t 11 fused to the transmembrane and cytoplasmic domain of the M6P/IGF-II re ceptor was transfected into mouse embryonic fibroblasts. The construct was expressed as a stable membrane protein which binds IGF-II with a 10-fold lo wer affinity as observed for the M6P/IGF-II receptor and is found at the ce ll surface and in endosomes. It mediates the internalization of IGF-II and its delivery to lysosomes, suggesting that it can function as a IGF-II mini -receptor controlling the extracellular IGF-II level.