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首页> 外文期刊>The FEBS journal >Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer
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Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer

机译：截断的甘露糖6-磷酸/胰岛素样生长因子II受体物种在癌症中的显性负作用。

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摘要

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 with by (View Interaction: , ) with by (View Interaction: , )
机译：甘露糖6磷酸/胰岛素样生长因子II受体（M6P / IGF2R）的寡聚化对于优化配体结合和内在化非常重要。 M6P / IGF2R是一种肿瘤抑制基因，表现出杂合性丧失，并在几种癌症中发生突变。我们测试了两个癌相关突变的潜在显性负性作用，这些突变在胞外域重复序列9和14中截断了M6P / IGF2R。我们的假设是截短受体与野生型/内源全长M6P / IGF2R共同表达会因异二聚体干扰而干扰M6P / IGF2R功能。免疫沉淀证实全长M6P / IGF2R和截短的受体（称为Rep9F和Rep14F）之间形成异二聚体复合物。值得注意的是，Rep9F或Rep14F的表达增加引起了细胞裂解液和质膜中全长M6P / IGF2Rs水平的降低，表明对受体利用率的显性负作用。全长M6P / IGF2R的丧失不是由于蛋白酶体或溶酶体降解的增加，而是由于细胞表面M6P / IGF2Rs的蛋白水解切割增加而引起的，其通过金属离子螯合剂抑制的机制导致胞外域释放。这些数据表明，M6P / IGF2R截短突变体可能通过减少全长M6P / IGF2Rs来执行肿瘤抑制功能（如受体配体（如胰岛素样生长因子II）的结合/内在化）而有助于癌症表型。结构化的数字摘要，带有by（查看交互：，），带有by（查看交互：，）

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