Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

The myotubularins are a large family of inositol polyphosphate 3-phosphatases that, despite having common substrates, subsume unique functions in cells that are disparate. The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2 ] at the D-3 position. Seven members are inactive because they lack the conserved cysteine residue in the CX 5 R motif required for activity. We studied a subfamily of homologous myotubularins, including myotubularin-related protein 6 (MTMR6), MTMR7, and MTMR8, all of which dimerize with the catalytically inactive MTMR9. Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity, wherein the MTMR6/R9 complex prefers PtdIns(3,5)P 2 as substrate; the MTMR8/R9 complex prefers PtdIns(3)P. MTMR9 increased the enzymatic activity of MTMR6 toward PtdIns(3,5)P 2 by over 30-fold, and enhanced the activity toward PtdIns(3)P by only 2-fold. In contrast, MTMR9 increased the activity of MTMR8 by 1.4-fold and 4-fold toward PtdIns (3,5)P 2 and PtdIns(3)P, respectively. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P 2 dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. Consequentially, the MTMR6/R9 complex serves to inhibit stress-induced apoptosis and the MTMR8/R9 complex inhibits autophagy.I nositol lipids play important roles in a variety of intracellular signaling pathways. In response to stimuli, the phosphoinositide profile is regulated by phospholipases, lipid kinases, and phosphatases. Understanding the roles of inositol signaling has expanded during the last decade and a number of these enzymes have been shown to cause diseases when mutated (1). The tumor-suppressor PTEN was discovered through positional cloning as being mutated in several types of cancer (2, 3). PTEN was subsequently shown to be a phosphatase, which dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to generate phosphatidylinositol 4,5-bisphosphate, an activity that is lost in patients with PTEN mutations (4, 5). Mutations in the inositol polyphosphate 5-phosphatase OCRL cause the X-linked disorder Lowe syndrome, which is associated with mental retardation, blindness, and renal failure (6). Mutations in myotubularin cause myotubular myopathy (7), and mutations in myotubularin-related protein 2 (MTMR2) and MTMR13 cause a form of Charcot Marie Tooth disease type 4B, a demyelinating neurodegenerative disorder (8, 9).The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity (10, 11) and 7 members that are inactive. Myotubularin proteins are not redundant and have unique functions within cells by regulating a specific pool of dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns (3...

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“…No cross-reactivity was detected. Immunoprecipitation and Western blotting were done as previously described (45).…”

Section: Methodsmentioning

confidence: 99%

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Zou¹,

Zhang²,

Marjanovic

et al. 2012

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

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“…Overexpression of TMEM55A increases EGF receptor degradation (1593). TMEM55B, on the other hand, was shown to control nuclear PtdIns5P levels and respond to DNA damage by nuclear translocation, activating the ING2 protein (522) and promoting p53-mediated cell death (1833).…”

Section: Tmem55mentioning

confidence: 99%

“…The nucleus-localized PIPKII␤ (263), most likely in the form of a heterodimer with the catalytically more active PIPKII␣ (1672), has an equally, if not more, important role in regulating PtdIns5P levels than controlling nuclear PtdIns(4,5)P 2 (522). PtdIns5P has been linked to stress-induced nuclear signaling and apoptosis (737,1833). The protein that responds to nuclear PtdIns5P is ING2, which specifically binds this lipid with its PHD domain.…”

Section: Nucleusmentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,393

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…TMEM55B has been further reported to dephosphorylate PtdIns(4,5)P 2 in vivo ( 115,116 ). In keeping with TMEM55 being unlikely to modulate the AKT pathway, there are no reports of TMEM55 involvement in cancer.…”

Section: Pten and Tpip Proteinsmentioning

confidence: 92%

Phosphatidylinositolphosphate phosphatase activities and cancer

Rudge

Wakelam

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org kinase pathways in regulating phosphoinositide signaling; however, all signaling pathways are subject to negative as well as positive control, pointing to a key role for inositol phospholipid phosphatases in cell and tissue regulation in health and disease. This review focuses upon this aspect of regulation, considering the importance of the many phosphatases that can act upon phosphoinositides, and we further consider the importance of each in malignancy. PHOSPHOINOSITIDE 3-KINASESIn mammals, the phosphoinositide 3-kinase (PI3K) isoforms responsible for phosphorylating the 3-hydroxyl group of the inositol headgroup of PtdIns, PtdIns(4)P, and PtdIns(4,5)P 2 have been divided into three classes: class I, class II, and class III.In response to activation of cell surface receptors, class I PI3Ks are responsible for phosphorylating PtdIns(4,5)P 2 to generate PtdIns(3,4,5)P 3 ( 3 ). There are four class I PI3Ks that exist as heterodimers of regulatory and catalytic subunits. The four distinct catalytic subunits, p110 ␣ , -␤ , -␥ , and -␦ , are further divided into class IA (p110 ␣ , -␤ , and -␦ ) and class IB (p110 ␥ ). Class IA PI3Ks bind the SH2 domain containing the p85 family of regulatory subunits (p85 ␣ , p85 ␤ , and p55) that bind to protein tyrosine phosphate residues in activated receptors, thus relieving p85-mediated Abstract Signaling through the phosphoinositide 3-kinase pathways mediates the actions of a plethora of hormones, growth factors, cytokines, and neurotransmitters upon their target cells following receptor occupation. Overactivation of these pathways has been implicated in a number of pathologies, in particular a range of malignancies. The tight regulation of signaling pathways necessitates the involvement of both stimulatory and terminating enzymes; inappropriate activation of a pathway can thus result from activation or inhibition of the two signaling arms . The focus of this review is to discuss, in detail, the activities of the identifi ed families of phosphoinositide phosphatase expressed in humans, and how they regulate the levels of phosphoinositides implicated in promoting malignancy. A series of tightly regulated lipid kinase and phosphatase enzyme activities coordinately convert phosphatidylinositol (PtdIns) into a network of phosphorylated derivatives, collectively called phosphoinositides. These differ in the number and position of the phosphate groups on the inositol head group: three PtdIns monophosphate isomers [PtdIns(3)P, PtdIns(4)P, and PtdIns(5)P], three PtdIns bisphosphate isomers [PtdIns(3,4)P 2 , PtdIns(3,5) P 2 , and PtdIns(4,5)P 2 ], and a single trisphosphate isomer [PtdIns(3,4,5)Phosphoinositide signaling is an extensively studied topic with clear evidence linking the pathway from the kinase to activation of AKT and TOR to a number of disease states. While these include malignancies, there is also strong evidence for other diseases, such as overgrowth syndromes. Most studies have focused upon the importance of the ...

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Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

Cited by 67 publications

References 23 publications

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Phosphatidylinositolphosphate phosphatase activities and cancer

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