(mentions CMT)Sequential Actions of Myotubularin Lipid Phosphatases Regulate End

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Mol Biol Cell. 2008 Jun 4.

Sequential Actions of Myotubularin Lipid Phosphatases Regulate

Endosomal PI(3)P and Growth Factor Receptor Trafficking.

Cao C, Backer JM, Laporte J, Bedrick EJ, Wandinger-Ness A.

Department of Pathology, University of New Mexico School of Medicine,

Albuquerque, NM 87131; Department of Molecular Pharmacology, Albert

Einstein College of Medicine, Bronx, NY 10461, USA; Department of

Molecular Pathology, Institut de Génétique et de Biologie Moléculaire

et Cellulaire (IGBMC), INSERM U596, CNRS UMR7104, Collège de France,

University Louis Pasteur de Strasbourg, 67404 Illkirch, France;

Department of Mathematics and Statistics and Department of Internal

Medicine, University of New Mexico, Albuquerque, NM 87131.

Monitoring Editor: Schmid Two different human diseases, X-

linked myotubular myopathy and Charcot-Marie-Tooth disease, result

from mutant MTM1 or MTMR2 lipid phosphatases. While events involved

in endosomal PI(3)P and PI(3,5)P2 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.