The Type Iα Inositol Polyphosphate 4-Phosphatase Generates and Terminates Phosphoinositide 3-Kinase Signals on Endosomes and the Plasma Membrane

Ivetac, Ivan; Munday, Adam D.; Kisseleva, Marina V.; Zhang, Xiangming; Luff, Susan E.; Tiganis, Tony; Whisstock, James C.; Rowe, Tony; Majerus, P.W.; Mitchell, Christina A.

doi:10.1091/mbc.e04-09-0799

Cited by 99 publications

(95 citation statements)

References 51 publications

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“…INPP4A activity was measured based on indirect estimation of PtdIns(3)P; briefly, lung cytosols were prepared using mitochondria isolation kit (MITO-ISO1, Sigma Chemical Co.) and were incubated (37 °C for 1 h) with 2 µM PtdIns(3,4)P2 (substrate of INPP4A) in reaction buffer 48 and reaction products were further incubated with PtdIns(3)P detector protein, followed by transferring final products to PtdIns(3)P-coated microplate for competitive enzyme-linked immunosorbent assay (ELISA), and the final INPP4A activity was expressed as PtdIns(3)P in picomoles produced from PtdIns(3,4)P2. Calpain activity was performed using a calpain activity assay kit (BIOvision, Inc., Mountain View, CA, USA).…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinase signalling output. Although inositol polyphosphate-4-phosphatase is known to regulate phosphoinositide-3 kinase signalling, little is known regarding its role in asthma pathogenesis. Here we show that modulation of inositol polyphosphate-4-phosphatase alters the severity of asthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositol polyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositol polyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpression of inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthma phenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severely aggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositol polyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airway hyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital in maintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase has an important role in modulating inflammatory response in asthma, and thus, uncover a new understanding of the complex interplay between inositol signalling and asthma, which could provide alternative strategies in asthma management. P hosphoinositide signalling, from phosphoinositide-3-kinase (PI3K) activation to Akt phosphorylation, critically regulates cellular functions, such as cell growth, differentiation, proliferation, survival and motility 1 . In response to growth factor stimuli, activation of PI(3)Ks leads to generation of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 at the plasma membrane. The intracellular concentration of PtdIns(3,4,5)P3 is controlled by a 3-phosphatase known as phosphatase and tensin homologue (PTEN) 2 or by 5-phosphatases (SHIP) 3 , resulting in the production of PtdIns(4,5)P2 and PtdIns(3,4)P2, respectively. PtdIns(3,4)P2, in turn, gets degraded by inositol polyphosphate-4-phosphatase (INPP4) to form PtdIns(3)P 4 . Genotypic variations in type I INPP4 (INPP4A), which is a regulatory checkpoint in phosphoinositide signalling, have previously been shown to be associated with increased risk of asthma 5,6 . Although other phosphoinositide phosphatases, PTEN and SHIP, have been shown to importantly regulate T-cell activation 7,8 , suppress B-cell lymphoma 9 and have protective roles in allergic airway inflammation (AAI) 10,11 , the functional role of INPP4A, in this context, is not known. As PtdIns(3,4)P2, but not PtdIns(3,4,5)P3, potently activates Akt 12 , INPP4A effectively terminates the PI3K-Akt signalling cascade.Asthma is characterized by episodic bronchoconstriction due to airway inflammation, remodelling and hyper-responsiveness 13 . Metabolic origins of asthma in obese subjects with minimal inflammatory cell infiltrate are an active topic of research 14 . Current understanding and treatment of asthma focuses on inhibiting airway inflamma...

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Section: Discussionmentioning

confidence: 99%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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“…PI3K activity generates phosphoinositides, which control cell survival, proliferation, migration and cellular trafficking (Cantley, 2002;Czech, 2003). Inositol polyphosphate-4-phosphatase is a regulator of PI3K, and it has been implicated in PI3K signaling at distinct subcellular junctions (Ivetac et al, 2005). Constitutive upregulation of cell-survival signaling mediated by PI3K/Akt has already been implicated in oncogenic transformation and tumor development, as it prevents apoptotic cell death during uncontrolled proliferation (Chang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Genes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expression

et al. 2007

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We investigated the effects of the human papillomavirus type 16 E5 oncogene on cellular gene expression in human epithelial cells using cDNA microarray. In a genome-wide microarray assay, the expression of 179 genes was found to be significantly altered due to E5 expression. The expression of lamin A/C was downregulated at protein level. The expression of protein kinase C-d and phosphoinositide-3-kinase proteins was found to be upregulated. We also observed increased motility of E5-expressing cells. We conclude that the E5 protein affects several cellular pathways involved in cell adhesion, cell motility and mitogenic signaling. These alterations may together lead to inhibition of apoptosis and facilitate the establishment of persistent infection in the epithelium.

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“…It has been reported that PtdIns(3,4,5)P 3 accumulation after cell stimulation is immediate and transient, whereas PtdIns(3,4)P 2 accumulation is slightly delayed and significantly more sustained in platelets (6,7). Also, unlike PtdIns(3,4,5)P 3 that is primarily present in the plasma membrane, PtdIns(3,4)P 2 may be localized at endosomes, intralumi-nal vesicles, endoplasmic reticulum, as well as the plasma membrane (8).…”

mentioning

confidence: 94%

Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains

Manna

Albanese

Park

et al. 2007

Journal of Biological Chemistry

130

150

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Phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) are lipid second messengers that regulate various cellular processes by recruiting a wide range of downstream effector proteins to membranes. Several pleckstrin homology (PH) domains have been reported to interact with PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 . To understand how these PH domains differentially respond to PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 signals, we quantitatively determined the PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 binding properties of several PH domains, including Akt, ARNO, Btk, DAPP1, Grp1, and C-terminal TAPP1 PH domains by surface plasmon resonance and monolayer penetration analyses. The measurements revealed that these PH domains have significant different phosphoinositide specificities and affinities. Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 specificities, respectively, whereas other PH domains exhibited less pronounced specificities. Also, the PH domains showed different degrees of membrane penetration, which greatly affected the kinetics of their membrane dissociation. Mutational studies showed that the presence of two proximal hydrophobic residues on the membrane-binding surface of the PH domain is important for membrane penetration and sustained membrane residence. When NIH 3T3 cells were stimulated with platelet-derived growth factor to generate PtdIns(3,4,5)P 3 , reversible translocation of Btk-PH, Grp1-PH, ARNO-PH, DAPP1-PH, and its L177A mutant to the plasma membrane was consistent with their in vitro membrane binding properties. Collectively, these studies provide new insight into how various PH domains would differentially respond to cellular PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 signals. Phosphoinositides (PIs)2 are mono-and polyphosphorylated derivatives of phosphatidylinositol (PtdIns) (1-3). AlthoughPIs are minor components of membrane lipids, they regulate a wide range of biological processes, including cell proliferation, cell survival, differentiation, signal transduction, cytoskeleton organization, and membrane trafficking (1-3). PIs regulate these cellular processes primarily by serving as site-specific membrane signals that mediate the membrane recruitment and regulation of effector proteins. The PI-mediated cellular processes allow exceptional spatiotemporal specificity because the spatial and temporal distribution of various PIs is dynamically and tightly regulated by a series of PI-modifying enzymes, such as phospholipases, lipid kinases, and lipid phosphatases, located in different cell membranes (1-3). For instance, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) are mainly found in the plasma membrane, whereas phosphatidylinositol 3-phosphate (PtdIns3P), phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 5-phosphate (PtdIns5P), and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2 ) are primarily present in endosomes, Golgi, nucl...

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The Type Iα Inositol Polyphosphate 4-Phosphatase Generates and Terminates Phosphoinositide 3-Kinase Signals on Endosomes and the Plasma Membrane

Cited by 99 publications

References 51 publications

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

Genes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expression

Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains

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