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The myotubularin family: from genetic disease to phosphoinositide metabolism.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP163, 67404 Illkirch Cedex, C.U. de, Strasbourg, France.
Trends in Genetics (Impact Factor: 11.6). 05/2001; 17(4):221-8. DOI: 10.1016/S0168-9525(01)02245-4
Source: PubMed

ABSTRACT The myotubularin-related genes define a large family of eukaryotic proteins, most of them initially characterized by the presence of a ten-amino acid consensus sequence related to the active sites of tyrosine phosphatases, dual-specificity protein phosphatases and the lipid phosphatase PTEN. Myotubularin (hMTM1), the founder member, is mutated in myotubular myopathy, and a close homolog (hMTMR2) was recently found mutated in a recessive form of Charcot-Marie-Tooth neuropathy. Although myotubularin was thought to be a dual-specificity protein phosphatase, recent results indicate that it is primarily a lipid phosphatase, acting on phosphatidylinositol 3-monophosphate, and might be involved in the regulation of phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane trafficking.

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    • "Indeed, PtdIns3P and PtdIns(3,5)P 2 are present on endosomal compartments where PtdIns3P predominates on early endosomes and PtdIns(3,5)P 2 on late endosomes (Cao et al., 2007; Cao et al., 2008; Laporte et al., 2002; Mochizuki and Majerus, 2003; Zhao et al., 2001). Additional studies using yeasts supported a role of myotubularin in vesicle homeostasis (Blondeau et al., 2000; Taylor et al., 2000a). "
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    • "The MTMR family of lipid phosphatases, composed of active and inactive subgroups, represents the largest protein tyrosine phosphatase (PTP) subfamily conserved from yeast to humans [2] [3]. Initially , MTM1 was the first family member shown to dephosphorylate the D3 position of PI(3)P in vitro and in vivo [4] [5]. "
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    • "The op309 mutation reduces MTM-1 phosphoinositide 3-phosphatase activity mtm-1 belongs to a large and disease-associated family of polyphosphoinositide (PPIn) 3-phosphatases, the myotubularins, which act on phosphatidylinositol-3-phosphate (PtdIns3P) and phosphatidylinositol-3,5-diphosphate [PtdIns(3,5)P 2 ] in mammals (Blondeau et al., 2000; Laporte et al., 2002b; Taylor et al., 2000; Tronchere et al., 2004; Walker et al., 2001). In addition to the phosphatase domain, all myotubularins contain a conserved Nterminal GRAM-PH (glucosyltransferases, Rab-like GTPase activators and myotubularins, pleckstrin-homology) domain, which has been suggested to mediate interaction with PPIn and membranes (Laporte et al., 2001). "
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