Production of Phosphatidylinositol 5-Phosphate by the Phosphoinositide 3-Phosphatase Myotubularin in Mammalian Cells

Tronchère, Hélène; Laporte, Jocelyn; Pendaries, Caroline; Chaussade, Claire; Liaubet, Laurence; Pirola, Luciano; Mandel, Jean‐Louis; Payrastre, Bernard

doi:10.1074/jbc.m311071200

Cited by 132 publications

(138 citation statements)

References 41 publications

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“…In vitro studies have shown that PI(5)P can be generated from PI(3,5)P 2 through the PI(3,5)P 2 3-phosphatase activity of members of the myotubularin family and related proteins including MTM1, MTMR1, MTMR2, MTMR3, MTMR6, and hJUMPY/MTMR14 (12)(13)(14)(15). In addition, PIKfyve/Fab1 can generate both PI(3,5)P 2 and PI(5)P in vitro (16).…”

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confidence: 99%

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Zhang¹,

Zolov²,

Chow³

et al. 2007

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

196

256

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The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P 2 synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P 2, is critical for the survival of neural cells.T he low-abundance signaling lipids, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ) and phosphatidylinositol 5-phosphate (PI(5)P), were discovered relatively recently (1-3). Because of their low abundance and the limited number of tools available for their study, relatively little is known about these lipids.An interesting property of PI(3,5)P 2 occurs in yeast, where a stimulus of hyperosmotic shock induces dramatic and transient changes in the levels of PI(3,5)P 2 . The levels of PI(3,5)P 2 transiently rise Ͼ20-fold (4). Within 1 minute, the levels rise 5-fold; by 5 minutes, they increase Ͼ20-fold; there is a short plateau of 10 min, and then PI(3,5)P 2 levels decrease at a rate similar to their increase. The rapid decrease in PI(3,5)P 2 levels occurs even though the cells remain in hyperosmotic media. Vacuole volume undergoes transient changes that parallel PI(3,5)P 2 levels. That these rapid and transient changes occur even in the presence of a sustained stimulus strongly suggests that PI(3,5)P 2 plays a major role in signaling pathways related to adaptation.Several proteins are required for the synthesis and turnover of PI(3,5)P 2 . PI(3,5)P 2 is synthesized from PI(3)P by the PI(3)P 5-kinase Fab1/PIKfyve/PIP5K3 (5, 6). Fab1 is stimulated by a regulatory complex that contains Vac14 (7, 8) and Fig4 (4, 9). Surprisingly, the Vac14/Fig4 complex plays two opposing roles in the regulation of steady-state levels of PI(3,5)P 2 . Vac14/Fig4 both activate Fab1 and also function in the breakdown of PI(3,5)P 2 through the lipid phosphatase activity of Fig4 (4, 9-11).In mammals, generation of PI(3,5)P 2 is predicted to impact PI(5)P production. In vitro studies have shown that PI(5)P can be generated from PI(3,5)P 2 through the PI(3,5)P 2 3-phosphatase activity of members of the myotubularin family and related proteins including MTM1, MTMR1, MTMR2, MTMR3, MTMR6, and hJUMPY/MTMR14 (12-15). In addition, PIKfyve/Fab1 can generate both PI(3,5)P 2 and PI(5)P in vitro (16). The source of PI(5)P in vivo has not been established. However, the generation of PI(5)P from either pathway requires PIKfyve/ Fab1 activity, either to produce the substrate for myotubularin [PI(3,5)P 2 ] or to produce PI(5...

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confidence: 99%

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Zhang¹,

Zolov²,

Chow³

et al. 2007

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

196

256

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“…2e), which suggests that PTPN14 regulates cell migration by modulating PTEN activity. The physiological role of myotubularin-related protein 1 (mtmr1) has not been clearly determined, although recent studies have shown that mtmr1 is a phosphatase, like myotubularin, and can dephosphorylate both PtdIns3P and PtdIns3,5P2 in vitro 38,39 , which suggests its possible involvement in the PI3K/PTEN/AKT pathway.…”

Section: Discussionmentioning

confidence: 99%

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

et al. 2014

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Lentiviral short hairpin RNA (shRNA)-mediated genetic screening is a powerful tool for identifying loss-of-function phenotype in mammalian cells. Here, we report the identification of 91 cell migration-regulating genes using unbiased genome-wide functional genetic selection. Individual knockdown or cDNA overexpression of a set of 10 candidates reveals that most of these cell migration determinants are strongly dependent on the PI3K/PTEN/ AKT pathway and on their downstream signals, such as FOXO1 and p70S6K1. ALK, one of the cell migration promoting genes, uniquely uses p55g regulatory subunit of PI3K, rather than more common p85 subunit, to trigger the activation of the PI3K-AKT pathway. Our method enables the rapid and cost-effective genome-wide selection of cell migration regulators. Our results emphasize the importance of the PI3K/PTEN/AKT pathway as a point of convergence for multiple regulators of cell migration.

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“…It is known that PtdIns-5-P levels increase in the nucleus during the G 1 phase of the cell cycle (17), increase in platelets in response to thrombin stimulation (18), and also increase after insulin stimulation of adipocytes (19). Hypoosmotic shock and histamine decrease PtdIns-5-P levels (7,20), and hyperosmotic shock increases PtdIns-5-P levels in L6 myotubes overexpressing the myotubularin protein MTM1 (9). Possible mechanisms of action of PtdIns-5-P signaling include the regulation of inositol lipid phosphatases, such as the myotubularins, and the regulation of the interaction between the putative tumor-suppressor protein ING2 and p53 (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…Recent work implied that a significant amount of cellular PtdIns-5-P might be regulated by lipid phosphatases rather than kinases, because overexpression of the relevant phosphatidylinositol kinases did not significantly affect PtdIns-5-P levels in HeLa or Cos7 cells (7). Candidate human phosphatases include some of the myotubularins that convert phosphatidylinositol-3,5-bisphosphate to 9).Some bacterial pathogens, such as Salmonella dublin, secrete virulence factors (SopB) that are inositol polyphosphate phosphatases into host cells to modulate the inositol-signaling pathways and improve their survival and propagation (10). The Shigella flexneri virulence factor IpgD is an inositol polyphosphate 4-phosphatase that converts PtdIns-4,5-P 2 to PtdIns-5-P, leading to an accumulation of PtdIns-5-P in cells infected with the pathogen.…”

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The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

Ungewickell

Hugge

Kisseleva

et al. 2005

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

103

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. Whereas the bacterial IpgD enzyme is known to catalyze this reaction, no such mammalian enzyme has been found. We have identified and characterized two previously undescribed human enzymes, PtdIns-4,5-P 2 4-phosphatase type I and type II, which catalyze the hydrolysis of PtdIns-4,5-P 2 to phosphatidylinositol-5-phosphate (PtdIns-5-P). Both enzymes are ubiquitously expressed and localize to late endosomal͞lysosomal membranes in epithelial cells. Overexpression of either enzyme in HeLa cells increases EGF-receptor degradation upon EGF stimulation.cell signaling ͉ lysosome ͉ phosphatidylinositol 5-phosphate I nositol-signaling molecules regulate many cellular processes, including actin cytoskeletal dynamics, apoptosis, cell division, and intracellular-membrane trafficking (1-4). Identification of the enzymes that regulate the levels of inositol second messengers is, therefore, important to understand how major cellular events are spatially and temporally coordinated.A large number of kinases and phosphatases have been described that regulate the levels of phosphatidylinositols in human cells (2,5). The production of PtdIns-5-P and its signaling functions are among the least well understood (6). Recent work implied that a significant amount of cellular PtdIns-5-P might be regulated by lipid phosphatases rather than kinases, because overexpression of the relevant phosphatidylinositol kinases did not significantly affect PtdIns-5-P levels in HeLa or Cos7 cells (7). Candidate human phosphatases include some of the myotubularins that convert phosphatidylinositol-3,5-bisphosphate to 9).Some bacterial pathogens, such as Salmonella dublin, secrete virulence factors (SopB) that are inositol polyphosphate phosphatases into host cells to modulate the inositol-signaling pathways and improve their survival and propagation (10). The Shigella flexneri virulence factor IpgD is an inositol polyphosphate 4-phosphatase that converts PtdIns-4,5-P 2 to PtdIns-5-P, leading to an accumulation of PtdIns-5-P in cells infected with the pathogen. Epithelial cells infected with Shigella flexneri exhibit membrane blebbing and actin cytoskeletal changes, indicating the importance of this reaction (11). Whether such a reaction normally occurs in mammalian cells and whether there are any endogenous enzymes that can catalyze this reaction have not been established.We now report the identification of two human PtdIns-4,5-P 2 4-phosphatases, PtdIns-4,5-P 2 4-phosphatase type I (PtdIns-4,5-P 2 4-Ptase I) and PtdIns-4,5-P 2 4-phosphatase type II (PtdIns-4,5-P 2 4-Ptase II). Both enzymes are ubiquitously expressed, localize to late endosomal͞lysosomal membranes, and appear to affect the lysosomal degradation of internalized plasma membrane receptors. We conclude that two different pathways exist in mammalian cells to degrade PtdIns-4,5-P 2 . One is catalyzed by inositol polyphosphate 5-phosphatases, leading to the production of PtdIns-4-P. The other pathway involves the type I and II PtdIns-4,5-P 2 4-Ptases and produces PtdIns-5-P. ¶ Antibodies and F...

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Production of Phosphatidylinositol 5-Phosphate by the Phosphoinositide 3-Phosphatase Myotubularin in Mammalian Cells

Cited by 132 publications

References 41 publications

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

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