Publications

• Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity.

  Walker D.M., Urbe S., Dove S.K., Tenza D., Raposo G., Clague M.J.

  Inositol lipids play key roles in many fundamental cellular processes that include growth, cell survival, motility, and membrane trafficking. Recent studies on the PTEN and Myotubularin proteins have underscored the importance of inositol lipid 3-phosphatases in cell function. Inactivating mutatio ... >> More

  Inositol lipids play key roles in many fundamental cellular processes that include growth, cell survival, motility, and membrane trafficking. Recent studies on the PTEN and Myotubularin proteins have underscored the importance of inositol lipid 3-phosphatases in cell function. Inactivating mutations in the genes encoding PTEN and Myotubularin are key steps in the progression of some cancers and in the onset of X-linked myotubular myopathy, respectively. Myotubularin-related protein 3 (MTMR3) shows extensive homology to Myotubularin, including the catalytic domain, but additionally possesses a C-terminal extension that includes a FYVE domain. We show that MTMR3 is an inositol lipid 3-phosphatase, with a so-far-unique substrate specificity. It is able to hydrolyze PtdIns3P and PtdIns3,5P2, both in vitro and when heterologously expressed in S. cerevisiae, and to thereby provide the first clearly defined route for the cellular production of PtdIns5P. Overexpression of a catalytically dead MTMR3 (C413S) in mammalian cells induces a striking formation of vacuolar compartments that enclose membranous structures that are highly concentrated in mutant proteins. << Less

  Curr. Biol. 11:1600-1605(2001) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3.

  Lorenzo O., Urbe S., Clague M.J.

  The myotubularins are a large family of phosphoinositide-specific phosphatases with substrate specificity for PtdIns3P and PtdIns(3,5)P(2). In addition to an N-terminal PH-GRAM (PH-G) domain and a signature catalytic domain shared with other family members, MTMR3 contains a C-terminal FYVE domain. ... >> More

  The myotubularins are a large family of phosphoinositide-specific phosphatases with substrate specificity for PtdIns3P and PtdIns(3,5)P(2). In addition to an N-terminal PH-GRAM (PH-G) domain and a signature catalytic domain shared with other family members, MTMR3 contains a C-terminal FYVE domain. We show that the FYVE domain of MTMR3 is atypical in that it neither confers endosomal localisation nor binds to the lipid PtdIns3P. Furthermore the FYVE domain is not required for in vitro enzyme activity of MTMR3. In contrast, the PH-GRAM domain is able to bind to phosphoinositide lipids, of which the allosteric regulator PtdIns5P is the preferred partner. Consequently, generation of PtdIns5P at the plasma membrane by ectopic expression of the bacterial phosphatase IpgD leads to a translocation of MTMR3 that requires the PH-G domain. Deletion of the PH-G domain leads to loss of activity of MTMR3 in vitro, and surprisingly, when combined with an active site mutation, accumulates the protein on the Golgi complex. << Less

  J Cell Sci 118:2005-2012(2005) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases.

  Schaletzky J., Dove S.K., Short B., Lorenzo O., Clague M.J., Barr F.A.

  Phosphoinositides control many different processes required for normal cellular function. Myotubularins are a family of Phosphatidylinositol 3-phosphate (PtdIns3P) phosphatases identified by the positional cloning of the MTM1 gene in patients suffering from X-linked myotubular myopathy and the MTM ... >> More

  Phosphoinositides control many different processes required for normal cellular function. Myotubularins are a family of Phosphatidylinositol 3-phosphate (PtdIns3P) phosphatases identified by the positional cloning of the MTM1 gene in patients suffering from X-linked myotubular myopathy and the MTMR2 gene in patients suffering from the demyelinating neuropathy Charcot-Marie-Tooth disease type 4B. MTM1 is a phosphatidylinositol phosphatase with reported specificity toward PtdIns3P, while the related proteins MTMR2 and MTMR3 hydrolyze both PtdIns3P and PtdIns(3,5)P2. We have investigated MTM1 and MTMR6 and find that they use PtdIns(3,5)P2 in addition to PtdIns3P as a substrate in vitro. The product of PtdIns(3,5)P2 hydrolysis, PtdIns5P, causes MTM1 to form a heptameric ring that is 12.5 nm in diameter, and it is a specific allosteric activator of MTM1, MTMR3, and MTMR6. A disease-causing mutation at arginine 69 of MTM1 falling within a putative pleckstrin homology domain reduces the ability of the enzyme to respond to PtdIns5P. We propose that the myotubularin family of enzymes utilize both PtdIns3P and PtdIns(3,5)P2 as substrates, and that PtdIns5P functions in a positive feedback loop controlling their activity. These findings highlight the importance of regulated phosphatase activity for the control of phosphoinositide metabolism. << Less

  Curr. Biol. 13:504-509(2003) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.