Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway.

Abstract

Myotubular myopathy (MTM1) is an X-linked disease, characterized by severe neonatal hypotonia and generalized muscle weakness, with pathological features suggesting an impairment in maturation of muscle fibres. The MTM1 gene encodes a protein (myotubularin) with a phosphotyrosine phosphatase consensus. It defines a family of at least nine genes in man, including the antiphosphatase hMTMR5/Sbf1 and hMTMR2, recently found mutated in a recessive form of Charcot-Marie-Tooth disease. Myotubularin shows a dual specificity protein phosphatase activity in vitro. We have performed an in vivo test of tyrosine phosphatase activity in Schizosaccharomyces pombe, indicating that myotubularin does not have a broad specificity tyrosine phosphatase activity. Expression of active human myotubularin inhibited growth of S.pombe and induced a vacuolar phenotype similar to that of mutants of the vacuolar protein sorting (VPS) pathway and notably of mutants of VPS34, a phosphatidylinositol 3-kinase (PI3K). In S.pombe cells deleted for the endogenous MTM homologous gene, expression of human myotubularin decreased the level of phosphatidylinositol 3-phosphate (PI3P). We have created a substrate trap mutant which shows relocalization to plasma membrane projections (spikes) in HeLa cells and was inactive in the S.pombe assay. This mutant, but not the wild-type or a phosphatase site mutant, was able to immunoprecipitate a VPS34 kinase activity. Wild-type myotubularin was also able to directly dephosphorylate PI3P and PI4P in vitro. Myotubularin may thus decrease PI3P levels by down-regulating PI3K activity and by directly degrading PI3P.

• Authors: F Blondeau, J Laporte, S Bodin, G Superti-Furga, B Payrastre, J L Mandel
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 9 Issue 15 Pg. 2223-9 (Sep 22 2000) ISSN: 0964-6906 [Print] England
• PMID: 11001925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphatidylinositol Phosphates
• phosphatidylinositol 3-phosphate
• Protein Tyrosine Phosphatases
• Protein Tyrosine Phosphatases, Non-Receptor
• myotubularin

Topics

• Animals
• Cell Line
• Down-Regulation
• Humans
• Myopathies, Structural, Congenital (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphatidylinositol Phosphates (metabolism)
• Precipitin Tests
• Protein Tyrosine Phosphatases (genetics, metabolism)
• Protein Tyrosine Phosphatases, Non-Receptor
• Schizosaccharomyces (enzymology, genetics, metabolism)
• Transfection