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.

Download full-text


Available from: Jocelyn Laporte, Aug 19, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 01/2012; 362:209-33. DOI:10.1007/978-94-007-5025-8_10 · 3.47 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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 · 3.34 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multicellular organisms use programmed cell death to eliminate unwanted or potentially harmful cells. Improper cell corpse removal can lead to autoimmune diseases. The development of interventional therapies that increase engulfment activity could represent an attractive approach to treat such diseases. Here, we describe mtm-1, the Caenorhabditis elegans homolog of human myotubularin 1, as a potential negative regulator of apoptotic cell corpse clearance. Loss of mtm-1 function leads to substantially reduced numbers of persistent cell corpses in engulfment mutants, which is a result of a restoration of engulfment function rather than of impaired or delayed programmed cell death. Epistatic analyses place mtm-1 upstream of the ternary GEF complex, which consists of ced-2, ced-5 and ced-12, and parallel to mig-2. Over-activation of engulfment results in the removal of viable cells that have been brought to the verge of death under limiting caspase activity. In addition, mtm-1 also promotes phagosome maturation in the hermaphrodite gonad, potentially through CED-1 receptor recycling. Finally, we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane.
    Development 05/2011; 138(10):2003-14. DOI:10.1242/dev.060012 · 6.27 Impact Factor
Show more