Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factorII receptor species in cancer

Oligomerization of the mannose 6-phosphate/insulin-like growth factorII 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-nega...

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Bibliographic Details
Published in:The FEBS journal 2012-08, Vol.279 (15), p.2695
Main Authors: Kreiling, Jodi L, Montgomery, Michelle A, Wheeler, Joseph R, Kopanic, Jennifer L, Connelly, Christopher M, Zavorka, Megan E, Allison, Jenna L, MacDonald, Richard G
Format: Article
Language:English
Subjects:
Cancer
Cellular biology
Insulin-like growth factors
Ligands
Molecular biology
Mutation
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Summary:Oligomerization of the mannose 6-phosphate/insulin-like growth factorII 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 factorII. Structured digital abstract * with by (View Interaction: , ) * with by (View Interaction: , ) [PUBLICATION ABSTRACT]
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2012.08652.x