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: 9.92). 05/2001; 17(4):221-8. DOI: 10.1016/S0168-9525(01)02245-4
Source: PubMed


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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    ABSTRACT: The level and turnover of phosphoinositides (PIs) are tightly controlled by a large set of PI-specific enzymes (PI kinases and phosphatases). Mammalian PI phosphatases are conserved through evolution and among this large family the dual-specificity phosphatase (PTP/DSP) are metal-independent enzymes displaying the amino acid signature Cys-X5-Arg-Thr/Ser (CX5RT/S) in their active site. Such catalytic site characterizes the myotubularin 3-phosphatases that dephosphorylate PtdIns3P and PtdIns(3,5)P (2) and produce PtdIns5P. Substrates of myotubularins have been implicated in endocytosis and membrane trafficking while PtdIns5P may have a role in signal transduction. As a paradox, 6 of the 14 members of the myotubularin family lack enzymatic activity and are considered as dead phosphatases. Several myotubularins have been genetically linked to human diseases: MTM1 is mutated in the congenital myopathy X-linked centronuclear or myotubular myopathy (XLCNM) and MTMR14 (JUMPY) has been linked to an autosomal form of such disease, while MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth (CMT) neuropathies. Furthermore, recent evidences from genetic association studies revealed that several other myotubularins could be associated to chronic disorders such as cancer and obesity, highlighting their importance for human health. Here, we discuss cellular and physiological roles of myotubularins and their implication in human diseases, and we present potential pathological mechanisms affecting specific tissues in myotubularin-associated diseases.
    Current topics in microbiology and immunology 10/2012; 362:209-33. DOI:10.1007/978-94-007-5025-8_10 · 4.10 Impact Factor
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    • "In C. elegans, six myotubularins have been identified, including three active phosphatases MTM-1, MTM-3, and MTM-6, and three dead phosphatases, MTM-5, MTM-9, and MTM-10 [11], [22]–[24], suggesting that the cooperation between active/dead phosphatases is conserved through evolution [17], [25], [26]. Specifically the MTM-6/MTM-9 complex regulated endosomal trafficking of the Wnt signaling complex [27]. "
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    ABSTRACT: Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.
    PLoS Genetics 04/2012; 8(4):e1002595. DOI:10.1371/journal.pgen.1002595 · 7.53 Impact Factor
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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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    ABSTRACT: Myotubularin related protein 2 (MTMR2) is a member of the myotubularin family of phosphoinositide lipid phosphatases. Although MTMR2 dephosphorylates the phosphoinositides PI(3)P and PI(3,5)P2, the phosphoinositide binding proteins that are regulated by MTMR2 are poorly characterized. In this study, phosphoinositide affinity chromatography coupled to mass spectrometry identified receptor mediated endocytosis 8 (RME-8) as a novel PI(3)P binding protein. RME-8 co-localized with the PI(3)P marker DsRed-FYVE, while the N-terminal region of RME-8 is required for PI(3)P and PI(3,5)P(2) binding in vitro. Depletion of PI(3)P by MTMR2 S58A or wortmannin treatment attenuated RME-8 endosomal localization and co-localization with EGFR on early endosomes. Our results suggest a model in which the localization of RME-8 to endosomal compartments is spatially mediated by PI(3)P binding and temporally regulated by MTMR2 activity.
    FEBS letters 06/2011; 585(12):1722-8. DOI:10.1016/j.febslet.2011.04.016 · 3.17 Impact Factor
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