Dominant‐negative effect of truncated mannose 6‐phosphate/insulin‐like growth factor II receptor species in cancer

Oligomerization of the mannose 6‐phosphate/insulin‐like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant‐negative effects of two cancer‐associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co‐expression of the truncated receptors with the wild‐type/endogenous full‐length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full‐length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full‐length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant‐negative effect on receptor availability. Loss of full‐length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell‐surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full‐length M6P/IGF2Rs to perform tumor‐suppressive functions such as binding/internalization of receptor ligands such as insulin‐like growth factor II. Structured digital abstract•   Rep9F physically interacts with WT‐M by anti tag coimmunoprecipitation (View Interaction: 1 , 2 ) •   Rep14F physically interacts with WT‐M by anti tag coimmunoprecipitation (View Interaction: 3 , 4 )