title: Myotubularin regulates the function of the late endosome through the gram domain-phosphatidylinositol 3,5-bisphosphate interaction.
abstract: Myotubularin and related proteins constitute a large and highly conserved family possessing phosphoinositide 3-phosphatase activity, although not all members possess this activity. This family contains a conserved region called the GRAM domain that is found in a variety of proteins associated with membrane-coupled processes and signal transduction. Mutations of myotubularin are found in X-linked myotubular myopathy, a severe muscle disease. Mutations in the GRAM domain are responsible for this condition, suggesting crucial roles for this region. Here, we show that the GRAM domain of myotubularin binds to phosphoinositide with the highest affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P(2)). In patients with myotubular myopathy, mutations in the myotubularin GRAM domain eliminate this binding, indicating that the PtdIns(3,5)P(2) binding ability of the GRAM (glucosyltransferases, Rablike GTPase activators and myotubularin) domain is crucial for the functions of myotubularin in vivo. Stimulation of epidermal growth factor recruits myotubularin to the late endosomal compartment in a manner dependent on the phosphoinositide binding. Overexpression of myotubularin inhibits epidermal growth factor receptor trafficking from late endosome to lysosome and induces the large endosomal vacuoles. Thus, our data suggest that myotubularin phosphatase physiologically functions in late endosomal trafficking and vacuolar morphology through interaction with PtdIns(3,5)P(2).
authors.affiliation: Department of Biochemistry, Institute of Medical Science, University of Tokyo and Japan Science and Technology Corporation, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tsujita
authors.forename: Toshiki
authors.initials: T
authors.lastname: Itoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ijuin
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Assia
authors.initials: A
authors.lastname: Shisheva
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
mesh_terms: D017124:Conserved Sequence; D011992:Endosomes / Q000201:enzymology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D014617:Vacuoles / Q000201:enzymology
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin