Skip to Main content Skip to Navigation
Journal articles

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

Abstract : 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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [53 references]  Display  Hide  Download
Contributor : Maité Peney <>
Submitted on : Tuesday, October 26, 2010 - 4:59:16 PM
Last modification on : Wednesday, October 14, 2020 - 3:49:04 AM
Long-term archiving on: : Thursday, January 27, 2011 - 2:23:18 AM


Publisher files allowed on an open archive




Canhong Cao, Jonathan Backer, Jocelyn Laporte, Edward Bedrick, Angela Wandinger-Ness. Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking.. Molecular Biology of the Cell, American Society for Cell Biology, 2008, 19 (8), pp.3334-46. ⟨10.1091/mbc.E08-04-0367⟩. ⟨inserm-00311079⟩



Record views


Files downloads