Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking
Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking
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DOI：
10.1091/mbc.e08-04-0367
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Wandinger-Ness, Angela
中科院分区：
文献类型：
--
作者：
Cao, Canhong;Backer, Jonathan M.;Wandinger-Ness, Angela
两种不同的人类疾病，x连锁肌小管肌病和沙克-玛丽-图斯病，是由MTM1或MTMR2脂质磷酸酶突变引起的。虽然参与内体PI(3) P和PI(3,5)P-2合成的事件在受体信号传导和降解中是非常重要的，但参与磷酸肌苷降解的酶及其在运输中的作用尚未完全确定。在这里，我们剖析了MTM1和MTMR2肌小管蛋白的功能，并确定它们如何促进内体PI(3) P稳态。通过sirna介导的肌小管蛋白耗竭模拟疾病中的功能丧失，过量的PI(3) P在早期（MTM1）和晚期（MTMR2）内体上积累。令人惊讶的是，增加的PI(3) P阻断了表皮生长因子受体从早期或晚期核内体的输出，这表明当MTM1或MTMR2突变时，不同核内体中信号受体的积累可能有助于独特的疾病病因。我们进一步证明，肌管蛋白直接结合III型PI 3-激酶复合物hVps34/hVps15导致磷酸酶失活。脂质激酶-磷酸酶的相互作用也排除了PI - 3激酶与Rab GTPase激活剂的相互作用。因此，独特的分子复合物控制着激酶和磷酸酶的激活，并局部调节离散核内体群体上的PI(3) P，从而为相关的人类肌肉和神经疾病提供了分子基础。
Two different human diseases, X-linked myotubular myopathy and Charcot-Marie-Tooth disease, result from mutant MTM1 or MTMR2 lipid phosphatases. Although events involved in endosomal PI(3) P and PI(3,5)P-2 synthesis are well established and pivotal in receptor signaling and degradation, enzymes involved in phosphoinositide degradation and their roles in trafficking are incompletely characterized. Here, we dissect the functions of the MTM1 and MTMR2 myotubularins and establish how they contribute to endosomal PI(3) P homeostasis. By mimicking loss of function in disease through siRNA-mediated depletion of the myotubularins, excess PI(3) P accumulates on early (MTM1) and late (MTMR2) endosomes. Surprisingly, the increased PI(3) P blocks the egress of epidermal growth factor receptors from early or late endosomes, suggesting that the accumulation of signaling receptors in distinct endosomes may contribute to the unique disease etiologies when MTM1 or MTMR2 are mutant. We further demonstrate that direct myotubularin binding to the type III PI 3-kinase complex hVps34/hVps15 leads to phosphatase inactivation. The lipid kinase-phosphatase interaction also precludes interaction of the PI 3-kinase with Rab GTPase activators. Thus, unique molecular complexes control kinase and phosphatase activation and locally regulate PI(3) P on discrete endosome populations, thereby providing a molecular rationale for related human myo- and neuropathies.