<i>Drosophila</i> Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions

Velichkova, Michaella; Juan, Joe; Kadandale, Pavan; Jean, Steve; Ribeiro, Inês; Raman, Vignesh; Stefan, Christopher J.; Kiger, Amy A.

doi:10.1083/jcb.200911020

Cited by 88 publications

(126 citation statements)

References 74 publications

(99 reference statements)

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“…Some of the family members, including MTM1, MTMR2, and MTMR9, translocate from cytoplasm to the Rac1-induced membrane ruffles in the PM (63). In Drosophila, myotubularin (mtm), an ortholog of both MTM1 and MTMR2, is involved in the PM dynamics in hemocytes (64). We showed here that MTMR6 and MTMR9 translocate to membrane ruffles in the PM and are essential for its dynamics during macropinocytosis.…”

Section: Discussionmentioning

confidence: 91%

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

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

109

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Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P 3 and PI(3,4) P 2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca 2+ -activated K + channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

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Section: Discussionmentioning

confidence: 91%

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

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

109

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“…It is probable that mammalian MTMRs have evolved non-redundant functions to spatially and temporally regulate such distinct events. Notably, Velichkova et al (47) also found that Pi3K68D, the Drosophila ortholog of the mammalian type-II PI 3-kinase PIK3C2B, was directly linked to a PI(3)P pool regulated by Drosophila mtm. While this manuscript was under revision, the same group also showed that depletion of Pi3K68D could suppress integrin trafficking defects associated with loss of mtm function (48).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent study by Velichkova et al (47) demonstrated that the sole Drosophila ortholog of the mammalian MTM1/ MTMR1/MTMR2 subfamily (mtm) regulates an endosomal pool of PI(3)P that plays distinct roles in endocytic trafficking and cortical remodeling. It is probable that mammalian MTMRs have evolved non-redundant functions to spatially and temporally regulate such distinct events.…”

Section: Discussionmentioning

confidence: 99%

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Razidlo¹,

Katafiasz²,

Taylor

2011

Journal of Biological Chemistry

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Myotubularin is a 3-phosphoinositide phosphatase that is mutated in X-linked myotubular myopathy, a severe neonatal disorder in which skeletal muscle development and/or regeneration is impaired. In this report we provide evidence that siRNA-mediated silencing of myotubularin expression markedly inhibits growth factor-stimulated Akt phosphorylation, leading to activation of caspase-dependent pro-apoptotic signaling in HeLa cells and primary human skeletal muscle myotubes. Myotubularin silencing also inhibits Akt-dependent signaling through the mammalian target of rapamycin complex 1 as assessed by p70 S6-kinase and 4E-BP1 phosphorylation. Similarly, phosphorylation of FoxO transcription factors is also significantly reduced in myotubularin-deficient cells. Our data further suggest that inhibition of Akt activation and downstream survival signaling in myotubularin-deficient cells is caused by accumulation of the MTMR substrate lipid phosphatidylinositol 3-phosphate generated from the type II phosphatidylinositol 3-kinase PIK3C2B. Our findings are significant because they suggest that myotubularin regulates Akt activation via a cellular pool of phosphatidylinositol 3-phosphate that is distinct from that generated by the type III phosphatidylinositol 3-kinase hVps34. Because impaired Akt signaling has been tightly linked to skeletal muscle atrophy, we hypothesize that loss of Akt-dependent growth/survival cues due to impaired myotubularin function may be a critical factor underlying the severe skeletal muscle atrophy characteristic of muscle fibers in patients with X-linked myotubular myopathy.Myotubularin is the archetypical member of a family of phosphoinositide 3-phosphatases. Mutations in the myotubularin gene are causative for X-linked recessive myotubular myopathy (XLMTM), 4 also known as "centronuclear myopathy." XLMTM is a severe neonatal disorder in which the maturation and/or regeneration of skeletal muscle fibers is compromised (1, 2). Myofibers from affected individuals display abnormal centrally located nuclei and are severely atrophic. Mice in which the myotubularin gene has been deleted exhibit a skeletal muscle phenotype consistent with that of XLMTM disease. Like XLMTM patients, early stages of myogenesis in these mice appear to occur normally, and it has been suggested that skeletal muscle maintenance or regeneration is affected rather than early myogenic differentiation (3). Mutations in two other MTMR family proteins, MTMR2 and MTMR13, are causative for the demyelinating peripheral neuropathy type 4B Charcot-Marie-Tooth disease (4 -6).The myotubularin-related protein (MTMR) family consists of 14 proteins including 8 catalytically active lipid phosphatases and 6 forms that are inactive due to germ-line substitutions of essential catalytic residues (7). Active MTMRs specifically remove the 3-phosphate moiety from phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ), generating phosphatidylinositol (PI) and phosphatidylinositol 5-phosphate (PI(5)P), respectively (...

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“…8 Different potential causes of the muscle weakness have been proposed for XLMTM, as triad structural defects, [9][10][11] unbalanced autophagy and protein homeostasis, [12][13][14] satellite cells alterations 15 or anomalies of the neuromuscular junction. 16,17 However, monitoring cellular pathological hallmarks in living mammalian models of XLMTM was not achieved to date, and the knowledge of the cellular pathology of XLMTM mainly relies on in vitro or ex vivo observations in mammalian models, 9,13,[18][19][20][21] or on data from more evolutionary-distant models as zebrafish, 10,17 drosophila, 22 C. elegans 23 or yeast. 18,24,25 Monitoring the structure of muscles in place is thus of importance to follow disease progression and potential amelioration upon treatments.…”

Section: Introductionmentioning

confidence: 99%

In vivo imaging of skeletal muscle in mice highlights muscle defects in a model of myotubular myopathy

et al. 2016

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Skeletal muscle structure and function are altered in different myopathies. However, the understanding of the molecular and cellular mechanisms mainly rely on in vitro and ex vivo investigations in mammalian models. In order to monitor in vivo the intracellular structure of the neuromuscular system in its environment under normal and pathological conditions, we set-up and validated non-invasive imaging of ear and leg muscles in mice. This original approach allows simultaneous imaging of different cellular and intracellular structures such as neuromuscular junctions and sarcomeres, reconstruction of the 3D architecture of the neuromuscular system, and video recording of dynamic events such as spontaneous muscle fiber contraction. Second harmonic generation was combined with vital dyes and fluorescentcoupled molecules. Skin pigmentation, although limiting, did not prevent intravital imaging. Using this versatile toolbox on the Mtm1 knockout mouse, a model for myotubular myopathy which is a severe congenital myopathy in human, we identified several hallmarks of the disease such as defects in fiber size and neuromuscular junction shape. Intravital imaging of the neuromuscular system paves the way for the follow-up of disease progression or/and disease amelioration upon therapeutic tests. It has also the potential to reduce the number of animals needed to reach scientific conclusions.

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Drosophila Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions

Abstract: Turnover of endosomal PI(3)P by mtm maintains endolysosomal homeostasis and cortical remodeling in Drosophila hemocytes during migration.

Cited by 88 publications

References 74 publications

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

In vivo imaging of skeletal muscle in mice highlights muscle defects in a model of myotubular myopathy

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