Myotubularin Regulates the Function of the Late Endosome through the GRAM Domain-Phosphatidylinositol 3,5-Bisphosphate Interaction

Tsujita, Kazuya; Itoh, Toshiki; Ijuin, Takeshi; Yamamoto, Akira; Shisheva, Assia; Laporte, Jocelyn; Takenawa, Tadaomi

doi:10.1074/jbc.m312294200

Cited by 139 publications

(154 citation statements)

References 36 publications

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“…It is likely that myotubularin proteins, which dephosphorylate PtdIns(3)P and PtdIns(3,5)P 2 at the D3 position, are involved in membrane trafficking. Overexpression of MTM1 leads to enlarged endosomal structures and delayed movement of the epidermal growth factor receptor into the lysosome, similar to the observation made when PtdIns(3)P or PtdIns(3,5)P 2 is depleted by mutations in PI3K or PIKfyve (40,41). A recent study with RNAi depletion of MTM1 also led to accumulation of the epidermal growth factor receptor in distinct endosomes, despite the increased level of PtdIns(3)P on early endosomes (42).…”

Section: Discussionmentioning

confidence: 53%

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Zou¹,

Zhang²,

Marjanovic

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The myotubularins are a large family of inositol polyphosphate 3-phosphatases that, despite having common substrates, subsume unique functions in cells that are disparate. The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2 ] at the D-3 position. Seven members are inactive because they lack the conserved cysteine residue in the CX 5 R motif required for activity. We studied a subfamily of homologous myotubularins, including myotubularin-related protein 6 (MTMR6), MTMR7, and MTMR8, all of which dimerize with the catalytically inactive MTMR9. Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity, wherein the MTMR6/R9 complex prefers PtdIns(3,5)P 2 as substrate; the MTMR8/R9 complex prefers PtdIns(3)P. MTMR9 increased the enzymatic activity of MTMR6 toward PtdIns(3,5)P 2 by over 30-fold, and enhanced the activity toward PtdIns(3)P by only 2-fold. In contrast, MTMR9 increased the activity of MTMR8 by 1.4-fold and 4-fold toward PtdIns (3,5)P 2 and PtdIns(3)P, respectively. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P 2 dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. Consequentially, the MTMR6/R9 complex serves to inhibit stress-induced apoptosis and the MTMR8/R9 complex inhibits autophagy.I nositol lipids play important roles in a variety of intracellular signaling pathways. In response to stimuli, the phosphoinositide profile is regulated by phospholipases, lipid kinases, and phosphatases. Understanding the roles of inositol signaling has expanded during the last decade and a number of these enzymes have been shown to cause diseases when mutated (1). The tumor-suppressor PTEN was discovered through positional cloning as being mutated in several types of cancer (2, 3). PTEN was subsequently shown to be a phosphatase, which dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to generate phosphatidylinositol 4,5-bisphosphate, an activity that is lost in patients with PTEN mutations (4, 5). Mutations in the inositol polyphosphate 5-phosphatase OCRL cause the X-linked disorder Lowe syndrome, which is associated with mental retardation, blindness, and renal failure (6). Mutations in myotubularin cause myotubular myopathy (7), and mutations in myotubularin-related protein 2 (MTMR2) and MTMR13 cause a form of Charcot Marie Tooth disease type 4B, a demyelinating neurodegenerative disorder (8, 9).The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity (10, 11) and 7 members that are inactive. Myotubularin proteins are not redundant and have unique functions within cells by regulating a specific pool of dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns (3...

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Section: Discussionmentioning

confidence: 53%

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Zou¹,

Zhang²,

Marjanovic

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This domain of about 70 amino acids is responsible for PtdIns(3,5)P2 binding. 21 Recently mitochondrial homeostasis in muscle fibers and regulation of the desmin cytoskeletal system was attributed to mytobularin. It was experimentally demonstrated that myotubularin interacts with desmin, and that this complex is disrupted by specific mutations in the MTM1 gene.…”

Section: Introductionmentioning

confidence: 99%

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin -a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligationdependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

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“…Members of this family contain a conserved region called the GRAM domain that is found in a variety of proteins associated with membrane-coupled processes and signal transduction (Tsujita et al, 2004). As compared to the day of standing heat, MTMR3 is upregulated in the cycling bovine endometrium at day 12 of the estrous cycle (Bauersachs et al, 2005).…”

Section: Genes Involved In Cell Adhesionmentioning

confidence: 99%

2 Identification of Genes Induced by the Conceptus in the Bovine Endometrium During the Pre-Implantation Period

Klein¹,

Bauersachs²,

Ulbrich³

et al. 2006

Reprod. Fertil. Dev.

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Early embryonic development, implantation, and maintenance of a pregnancy are critically dependent on an intact embryo-maternal communication. So far, only few signals involved in this dialogue have been identified. In ruminants, interferon tau (IFN�) plays a key role in the process of maternal recognition of pregnancy by exhibiting antiluteolytic activity. Even though many experimental findings indicate a pivotal role of IFN� in the context of embryo-maternal communication in ruminants, a number of other systems may be involved. To identify genes induced in the bovine endometrium by the signaling of the embryo, a combination of subtracted cDNA libraries and cDNA array hybridization was applied. Monozygotic twin pairs (n = 5) were used as the biological model. Pregnancy was created in one twin by transferring two in vitro-produced embryos on Day 7 of the estrous cycle; the other twin received a sham embryo transfer. Pregnant and nonpregnant twins were slaughtered at Day 18; endometrial tissue samples were recovered and processed for transcriptome analysis as described (Bauersachs et al. 2005 J. Mol. Endocrinol. 34, 889-908). Screening of 4608 clones of two subtracted libraries revealed 90 different up-regulated genes and mRNAs, of which almost 50% are known to be stimulated by type I interferons. Among these interferon-stimulated genes, the ISG15 system is assumed to be of particular interest, and several components were studied in more detail using in situ hybridization. The pattern of mRNA expression suggests that modification of endometrial proteins through ISG15ylation plays a fundamental role during the pre-implantation period. A classification of the identified genes based on Gene Ontologies revealed the prevalence of genes involved in regulation of gene expression, cell communication, cell growth, cell differentiation, cell proliferation, and cell adhesion, and also the prevalence of genes with immune-related functions. These results underline the intense response of the endometrium to the presence of a conceptus, culminating in the preparation of the maternal environment for embryonic implantation. Further, for eleven selected genes the expression in the endometrium was quantified by the use of real-time RT-PCR. Overall, the results of quantitative RT-PCR and array hybridization correlated very well. To our knowledge this study provides the first holistic gene expression analysis of the bovine endometrium during the pre-implantation period. The results underline the importance of IFN� as an embryo-derived pregnancy recognition signal and depict the molecular mechanisms at the mRNA level underlying the intense embryo-maternal dialog taking place at Day 18 of gestation.

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Myotubularin Regulates the Function of the Late Endosome through the GRAM Domain-Phosphatidylinositol 3,5-Bisphosphate Interaction

Cited by 139 publications

References 36 publications

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

2 Identification of Genes Induced by the Conceptus in the Bovine Endometrium During the Pre-Implantation Period

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