Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking

被引:104
作者
Cao, Canhong [1 ]
Backer, Jonathan M. [4 ]
Laporte, Jocelyn [5 ]
Bedrick, Edward J. [2 ,3 ]
Wandinger-Ness, Angela [1 ]
机构
[1] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA
[2] Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA
[3] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA
[4] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
[5] Univ Strasbourg 1, Dept Mol Pathol, UMR7104, Coll France,IGBMC,INSERM,CNRS,U596, F-67404 Illkirch Graffenstaden, France
基金
美国国家科学基金会;
关键词
D O I
10.1091/mbc.E08-04-0367
中图分类号
Q2 [细胞生物学];
学科分类号
071009 [细胞生物学]; 090102 [作物遗传育种];
摘要
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.
引用
收藏
页码:3334 / 3346
页数:13
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