title: Functional redundancy in the myotubularin family.
abstract: Myotubularin-related genes define a novel highly conserved family of eukaryotic proteins of at least 11 human members. The hMTM1 gene that codes for myotubularin is mutated in X-linked myotubular myopathy, a severe congenital disease. Recently, we and others have characterized myotubularin as a potent and specific phosphatidylinositol 3-phosphate 3-phosphatase. In the present study we investigated the lipid phosphatase activity and the subcellular localization of two other members of the family, hMTMR2 protein that is mutated in the demyelinating neuropathy Charcot-Marie-Tooth type 4B and the FYVE-finger containing hMTMR3 protein. Our results show that both proteins are potent phosphatidylinositol 3-phosphate 3-phosphatases either in vitro or in yeast where they interfered with vesicular trafficking. Their localization is mainly cytoplasmic, with however strong labeling of Rac-inducible plasma membrane ruffles. The fact that the ubiquitously expressed hMTM1 and hMTMR2 genes are involved in different pathologies indicates that despite their shared enzymatic activity, they are not functionally redundant, at least in certain cell types. This might be explained by subtle differences in expression and/or in recruitment and regulation at their specific site of action.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, C.U. de Strasbourg, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: Laurence
authors.initials: L
authors.lastname: Liaubet
authors.forename: François
authors.initials: F
authors.lastname: Blondeau
authors.forename: Hélène
authors.initials: H
authors.lastname: Tronchère
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D006801:Humans; D008856:Microscopy, Fluorescence; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C408986:MTMR2 protein, human; C444436:MTMR3 protein, human; C099588:myotubularin