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Vol. 19, Issue 8, 3334-3346, August 2008

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Sequential Actions of Myotubularin Lipid Phosphatases Regulate Endosomal PI(3)P and Growth Factor Receptor Trafficking

Canhong Cao^*, Jonathan M. Backer, Jocelyn Laporte, Edward J. Bedrick, and Angela Wandinger-Ness^*

*Department of Pathology, University of New Mexico School of Medicine and Department of Mathematics and Statistics and Department of Internal Medicine, Albuquerque, NM 87131; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; and Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U596, Centre National de la Recherche Scientifique UMR7104, Collège de France, University Louis Pasteur de Strasbourg, 67404 Illkirch, France

Submitted April 9, 2008; Revised May 19, 2008; Accepted May 22, 2008
Monitoring Editor: Sandra Schmid

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)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.

Address correspondence to: Angela Wandinger-Ness (wness{at}unm.edu)

Abbreviations used: CMT, Charcot-Marie-Tooth; EEA1, early endosome antigen 1; EGFR, epidermal growth factor receptor; FYVE, Fab1p, YOTB, Vac1p and EEA1 domain; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRAM, glucosyltransferases, Rablike GTPase activators and myotubularin domain; GroP, glycerophosphoinositol phosphates; HEAT, Huntington, EF-3, PR65/A and mTOR domain; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; hVps, human vacuolar protein sorting; MTM1, myotubularin 1; MTMR2, myotubularin-related protein 2; MVB, multivesicular body; (PI(3)P), phosphatidylinositol 3-phosphate; (PI(3,5)P₂), phosphatidylinositol 3,5-phosphate; PKD, protein kinase domain; Tsg, tumor susceptibility gene; WD40, beta-propeller domain or beta-transducin repeats.