The PtdIns3‐phosphatase MTMR3 interacts with mTORC1 and suppresses its activity

Hao, Feike; Itoh, Takashi; Morita, Eiji; Shirahama-Noda, Kanae; Yoshimori, Tamotsu; Noda, Tetsuji

doi:10.1002/1873-3468.12048

Cited by 28 publications

(24 citation statements)

References 48 publications

(79 reference statements)

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“…MTMR7 decreased phosphorylation of ERK1/2 by MEK1/2 on 202/185TEY204/187 and of AKT on S473/T308 residues. Hence, MTMR7 did not block single mTORC1/2 complexes, as described for MTM1 [19, 20] or MTMR3 [21], what would have abrogated phosphorylation exclusively on either SER473, which is part of the AKT-mTORC2 feed forward loop, or THR308, which is targeted by PI3K-PDK1. Instead, MTMR7 inhibited upstream components in these pathways resulting in a decreased production of the lipid second messenger PI(3)P. MTMR8 binds PI3K thereby reducing PI3K activity [22].…”

Section: Discussionmentioning

confidence: 96%

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

et al. 2016

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Phosphoinositide (PIP) phosphatases such as myotubularins (MTMs) inhibit growth factor receptor signaling. However, the function of myotubularin-related protein 7 (MTMR7) in cancer is unknown. We show that MTMR7 protein was down-regulated with increasing tumor grade (G), size (T) and stage (UICC) in patients with colorectal cancer (CRC) (n=1786). The presence of MTMR7 in the stroma correlated with poor prognosis, whereas MTMR7 expression in the tumor was not predictive for patients' survival. Insulin reduced MTMR7 protein levels in human CRC cell lines, and CRC patients with type 2 diabetes mellitus (T2DM) or loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) had an increased risk for MTMR7 loss. Mechanistically, MTMR7 lowered PIPs and inhibited insulin-mediated AKT-ERK1/2 signaling and proliferation in human CRC cell lines. MTMR7 provides a novel link between growth factor signaling and cancer, and may thus constitute a potential marker or drug target for human CRC.

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Section: Discussionmentioning

confidence: 96%

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

et al. 2016

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“…Another study (Taguchi‐Atarashi et al., ) uncovered a negative regulatory role of MTMR3 in autophagosome formation. Further studies (Hao et al., ) showed that MTMR3 associated with mTOR and suppressed its activity in manners independent of MTMR3 enzymatic activity, suggesting the bimodal actions of MTMR3 in the autophagy regulation. Notably, MTMR3 was found to interact with MTMR4 in cells.…”

Section: Discussionmentioning

confidence: 98%

“…However, the subcellular localization of MTMR4 is not fully understood. Moreover, several MTMRs have been implicated in autophagy (Al‐Qusairi et al., ; Hao et al., ; Liu, Lv, Liu, Qu, & Shen, ; Noda, Matsunaga, Taguchi‐Atarashi, & Yoshimori, ; Taguchi‐Atarashi et al., ; Vergne & Deretic, ; Vergne et al., ; Zou et al., ) and lysosomal storage disorder‐related human diseases. MTM1 has been shown to be mutated in congenital X‐linked centronuclear or myotubular myopathy (XLCNM) (Kioschis et al., ), while MTMR2 and MTMR13 have been shown to be mutated in Charcot‐Marie‐Tooth (CMT) neuropathy (Azzedine et al., ).…”

Section: Introductionmentioning

confidence: 99%

MTMR4, a phosphoinositide‐specific 3’‐phosphatase, regulates TFEB activity and the endocytic and autophagic pathways

et al. 2018

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Phosphatidylinositol 3-phosphate (PI(3)P) is the predominant phosphoinositide species in early endosomes and autophagosomes, in which PI(3)P dictates traffic of these organelles. Phosphoinositide levels are tightly regulated by lipid-kinases and -phosphatases; however, a phosphatase that converts PI(3)P back to phosphatidylinositol in the endosomal and autophagosomal compartments is not fully understood. We investigated the subcellular distribution and functions of myotubularin-related protein-4 (MTMR4), which is distinct among other MTMRs in that it possesses a PI(3)P-binding FYVE domain, in lung alveolar epithelium-derived A549 cells. MTMR4 was localized mainly in late endosomes and autophagosomes. MTMR4 knockdown markedly suppressed the motility, fusion, and fission of PI(3)P-enriched structures, resulting in decreases in late endosomes, autophagosomes, and lysosomes, and enlargement of PI(3)P-enriched early and late endosomes. In amino acid- and serum-starved cells, MTMR4 knockdown decreased both autophagosomes and autolysosomes and markedly increased PI(3)P-containing autophagosomes and late endosomes, suggesting that the fusion with lysosomes of autophagosomes and late endosomes might be impaired. Notably, MTMR4 knockdown inhibited the nuclear translocation of starvation stress responsive transcription factor-EB (TFEB) with reduced expression of lysosome-related genes in starved cells. These findings indicate that MTMR4 is essential for the integrity of endocytic and autophagic pathways.

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“…Myotubularin‐related protein 3 (MTMR3) is a PtdIns3P phosphatase found to be important for autophagy . MTMR3 depletion or overexpression of a phosphatase‐deficient mutant, lead to increased autophagosome formation, whereas overexpression of wild‐type MTMR3 resulted in smaller autophagosomes and a net reduction in autophagic activity (Fig.…”

Section: Ptdins‐binding Domains and The Autophagy Proteins That Contamentioning

confidence: 99%

“…Upon nutrient depletion, mTORC1 activity decreases, leading to ULK1 dephosphorylation, activation, and autophosphorylation , as well as its phosphorylation of ATG13, FIP200, Beclin1, and VPS34 . Both wild‐type and phosphatase‐deficient MTMR3 inhibit mTORC1 activity, indicating that this protein may regulate autophagy both at the level of PtdIns3P and mTORC1 . There are 16 different MTMR proteins, nine of which possess catalytic activity, dephosphorylating PtdIns3P and PtdIns(3,5)P 2 at the D‐3 position.…”

Section: Ptdins‐binding Domains and The Autophagy Proteins That Contamentioning

confidence: 99%

Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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The PtdIns3‐phosphatase MTMR3 interacts with mTORC1 and suppresses its activity

Cited by 28 publications

References 48 publications

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

MTMR4, a phosphoinositide‐specific 3’‐phosphatase, regulates TFEB activity and the endocytic and autophagic pathways

Phosphoinositide‐binding proteins in autophagy

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