The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes
The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes
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DOI：
10.1038/emboj.2008.308
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发表时间：
2009-03-04
期刊：
影响因子：
11.4
通讯作者：
Okada, Masato
中科院分区：
文献类型：
--
作者：
Nada, Shigeyki;Hondo, Akihiro;Okada, Masato
内体动力学的调节对于基本的细胞功能是至关重要的，例如营养摄入/消化、膜蛋白循环、细胞迁移和细胞内信号传导。在这里，我们表明，一种新的脂筏衔接蛋白，p18，参与控制内体动力学锚定的MEK 1-ERK通路晚期内体。p18通过其N末端独特区域锚定在晚期内体的脂筏上。p18（-/-）小鼠是胚胎致死的，并且在内脏内胚层中的内体/溶酶体组织和膜蛋白转运中具有严重缺陷。p18（-/-）细胞通过核周区室表现出明显的内体动力学缺陷，例如溶酶体的异常分布和/或加工以及Rab 11阳性再循环内体的循环受损。p18特异性结合p14-MP 1复合物，一种MEK 1的支架。p18功能的丧失将p14-MP 1复合物从晚期内体中排除，导致MEK-ERK活性的下调。这些结果表明，脂筏适配器p18是必不可少的锚定MEK-ERK通路的晚期内体，并揭示了新的光内体MEK-ERK通路的作用，在控制内体动力学。
The regulation of endosome dynamics is crucial for fundamental cellular functions, such as nutrient intake/digestion, membrane protein cycling, cell migration and intracellular signalling. Here, we show that a novel lipid raft adaptor protein, p18, is involved in controlling endosome dynamics by anchoring the MEK1-ERK pathway to late endosomes. p18 is anchored to lipid rafts of late endosomes through its N-terminal unique region. p18(-/-) mice are embryonic lethal and have severe defects in endosome/lysosome organization and membrane protein transport in the visceral endoderm. p18(-/-) cells exhibit apparent defects in endosome dynamics through perinuclear compartment, such as aberrant distribution and/or processing of lysosomes and impaired cycling of Rab11-positive recycling endosomes. p18 specifically binds to the p14-MP1 complex, a scaffold for MEK1. Loss of p18 function excludes the p14-MP1 complex from late endosomes, resulting in a downregulation of the MEK-ERK activity. These results indicate that the lipid raft adaptor p18 is essential for anchoring the MEK-ERK pathway to late endosomes, and shed new light on a role of endosomal MEK-ERK pathway in controlling endosome dynamics.