Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia
Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia
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DOI：
10.1242/jcs.082610
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发表时间：
2011-04-15
影响因子：
4
通讯作者：
Lappalainen, Pekka
中科院分区：
文献类型：
--
作者：
Saarikangas, Juha;Mattila, Pieta K.;Lappalainen, Pekka
MIM/MTSS1是一种组织特异性的质膜动力学调节器，其表达水平的改变与肿瘤转移有关。MIM通过其I-bar结构域使富含磷酸肌醇的膜变形，并通过其WH2结构域与肌动蛋白单体相互作用。最近的工作表明，MIM还增强了Sonic hedgehog(Shh)诱导的基因表达。在这里，我们产生了MIM突变小鼠，并发现全长MIM蛋白对胚胎发育是必不可少的。然而，MIM缺陷小鼠表现出严重的尿液浓度缺陷，这是由于肾上皮细胞间连接的完整性受损导致的，这导致骨骼异常和终末期肾功能衰竭。在培养的肾上皮细胞(MDCK)中，MIM动态定位于黏附连接，促进Arp2/3介导的肌动蛋白微丝组装。这种活性依赖于MIM与膜和肌动蛋白单体相互作用的能力。此外，小鼠模型和细胞培养实验的结果表明，全长MIM对Shh信号不是至关重要的，至少在胚胎发育过程中是这样。总之，这些数据表明，MIM调节肌动蛋白细胞骨架和质膜之间的相互作用，以促进肾上皮细胞间接触的维持。
MIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through its I-BAR domain and interacts with actin monomers through its WH2 domain. Recent work proposed that MIM also potentiates Sonic hedgehog (Shh)-induced gene expression. Here, we generated MIM mutant mice and found that full-length MIM protein is dispensable for embryonic development. However, MIM-deficient mice displayed a severe urinary concentration defect caused by compromised integrity of kidney epithelia intercellular junctions, which led to bone abnormalities and end-stage renal failure. In cultured kidney epithelial (MDCK) cells, MIM displayed dynamic localization to adherens junctions, where it promoted Arp2/3-mediated actin filament assembly. This activity was dependent on the ability of MIM to interact with both membranes and actin monomers. Furthermore, results from the mouse model and cell culture experiments suggest that full-length MIM is not crucial for Shh signaling, at least during embryogenesis. Collectively, these data demonstrate that MIM modulates interplay between the actin cytoskeleton and plasma membrane to promote the maintenance of intercellular contacts in kidney epithelia.