Myotubularin, a Protein Tyrosine Phosphatase Mutated in Myotubular Myopathy, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3-Phosphate

The lipid second messenger phosphatidylinositol 3-phosphate [PI(3)P] plays a crucial role in intracellular membrane trafficking. We report here that myotubularin, a protein tyrosine phosphatase required for muscle cell differentiation, is a potent PI(3)P phosphatase. Recombinant human myotubularin s...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2000-08, Vol.97 (16), p.8910-8915
Main Authors: Taylor, Gregory S., Maehama, Tomohiko, Dixon, Jack E.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biochemistry
Biological Sciences
Cell Line
Cells
Elution
Enzymes
HEK293 cells
Humans
Inositols
Lipids
Membranes
Muscles - cytology
Muscles - enzymology
Muscular diseases
Mutation
Myopathies, Structural, Congenital - metabolism
Phosphatases
Phosphates
Phosphatidylinositol Phosphates - metabolism
Phosphatidylinositols
Phosphorylation
Protein Tyrosine Phosphatases - metabolism
Protein Tyrosine Phosphatases, Non-Receptor
Proteins
Recombinant Proteins - metabolism
Signal Transduction
Yeasts
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Summary:The lipid second messenger phosphatidylinositol 3-phosphate [PI(3)P] plays a crucial role in intracellular membrane trafficking. We report here that myotubularin, a protein tyrosine phosphatase required for muscle cell differentiation, is a potent PI(3)P phosphatase. Recombinant human myotubularin specifically dephosphorylates PI(3)P in vitro. Overexpression of a catalytically inactive substrate-trapping myotubularin mutant (C3755) in human 293 cells increases PI(3)P levels relative to that of cells overexpressing the wild-type enzyme, demonstrating that PI(3)P is a substrate for myotubularin in vivo. In addition, a Saccharomyces cerevisiae strain in which the myotubularin-like gene (YJR110w) is disrupted also exhibits increased PI(3)P levels. Both the recombinant yeast enzyme and a human myotubularin-related protein (KIAA0371) are able to dephosphorylate PI(3)P in vitro, suggesting that this activity is intrinsic to all myotubularin family members. Mutations in the MTM1 gene that cause human myotubular myopathy dramatically reduce the ability of the phosphatase to dephosphorylate PI(3)P. Our findings provide evidence that myotubularin exerts its effects during myogenesis by regulating cellular levels of the inositol lipid PI(3)P.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.160255697