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Journal articles on the topic 'Phosphatidylinositol-(3,4,5)-triphosphate'

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Published: 4 June 2021
Last updated: 8 February 2022

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1

Saito, Tsugumichi, Shuichi Okada, Atsushi Nohara, et al. "Syntaxin4 Interacting Protein (Synip) Binds Phosphatidylinositol (3,4,5) Triphosphate." PLoS ONE 7, no. 8 (2012): e42782. http://dx.doi.org/10.1371/journal.pone.0042782.

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Manna, Prasenjit, and Sushil K. Jain. "Phosphatidylinositol-3,4,5-Triphosphate and Cellular Signaling: Implications for Obesity and Diabetes." Cellular Physiology and Biochemistry 35, no. 4 (2015): 1253–75. http://dx.doi.org/10.1159/000373949.

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Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) is one of the most important phosphoinositides and is capable of activating a wide range of proteins through its interaction with their specific binding domains. Localization and activation of these effector proteins regulate a number of cellular functions, including cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. Phosphoinositides have been investigated as an important agonist-dependent second messenger in the regulation of diverse physiological events depending upon the phosphorylation status of their inositol group. Dysregulation in formation as well as metabolism of phosphoinositides is associated with various pathophysiological disorders such as inflammation, allergy, cardiovascular diseases, cancer, and metabolic diseases. Recent studies have demonstrated that the impaired metabolism of PtdIns(3,4,5)P3 is a prime mediator of insulin resistance associated with various metabolic diseases including obesity and diabetes. This review examines the current status of the role of PtdIns(3,4,5)P3 signaling in the regulation of various cellular functions and the implications of dysregulated PtdIns(3,4,5)P3 signaling in obesity, diabetes, and their associated complications.
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Konradsson, Peter, Daina Lezdins, and Katinka Ruda. "Synthesis of Glycosyl Phosphatidylinositol Anchors and Phosphatidyl-inositol-(3,4,5)-triphosphate." Carbohydrate Polymers 34, no. 4 (1997): 428. http://dx.doi.org/10.1016/s0144-8617(97)87360-2.

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4

Karlsson, Thomas, Altanchimeg Altankhuyag, Olena Dobrovolska, Diana C. Turcu, and Aurélia E. Lewis. "A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction." Biochemical Journal 473, no. 14 (2016): 2033–47. http://dx.doi.org/10.1042/bcj20160274.

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We reveal the identification of a polybasic motif necessary for polyphosphoinositide interaction and nucleolar targeting of ErbB3 binding protein 1 (EBP1). EBP1 interacts directly with phosphatidylinositol(3,4,5)-triphosphate and their association is detected in the nucleolus, implying regulatory roles of nucleolar processes.
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5

Tobias, Irene S., Manuel Kaulich, Peter K. Kim та ін. "Protein kinase Cζ exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation". Biochemical Journal 473, № 4 (2016): 509–23. http://dx.doi.org/10.1042/bj20151013.

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PKCζ is phosphorylated co-translationally by mammalian target of rapamycin complex 2 (mTORC2) at the turn motif with subsequent phosphorylation by phosphoinositide-dependent kinase-1 (PDK1) at the activation loop to yield a constitutively phosphorylated species whose global cellular activity is phosphatidylinositol-3,4,5-triphosphate (PIP3)-insensitive.
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Gaffney, Piers R. J., and Colin B. Reese. "ChemInform Abstract: Synthesis of Naturally Occurring Phosphatidylinositol 3,4,5-Triphosphate [PtdIns(3,4,5)P3] and Its Diastereoisomers." ChemInform 32, no. 19 (2001): no. http://dx.doi.org/10.1002/chin.200119177.

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Miao, Benchun, and Alexei Degterev. "Targeting phospshatidylinositol 3-kinase signaling with novel phosphatidylinositol 3,4,5-triphosphate antagonists." Autophagy 7, no. 6 (2011): 650–51. http://dx.doi.org/10.4161/auto.7.6.15248.

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8

Zhang, P., Y. Wang, H. Sesaki, and M. Iijima. "Proteomic identification of phosphatidylinositol (3,4,5) triphosphate-binding proteins in Dictyostelium discoideum." Proceedings of the National Academy of Sciences 107, no. 26 (2010): 11829–34. http://dx.doi.org/10.1073/pnas.1006153107.

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9

Ande, Sudharsana R., and Suresh Mishra. "Prohibitin interacts with phosphatidylinositol 3,4,5-triphosphate (PIP3) and modulates insulin signaling." Biochemical and Biophysical Research Communications 390, no. 3 (2009): 1023–28. http://dx.doi.org/10.1016/j.bbrc.2009.10.101.

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10

Takahashi, Kazuhide, Tacu Tanaka, and Katsuo Suzuki. "Directional control of WAVE2 membrane targeting by EB1 and phosphatidylinositol 3,4,5-triphosphate." Cellular Signalling 22, no. 3 (2010): 510–18. http://dx.doi.org/10.1016/j.cellsig.2009.11.005.

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11

Simpson, Laura, Jing Li, Danny Liaw, et al. "PTEN Expression Causes Feedback Upregulation of Insulin Receptor Substrate 2." Molecular and Cellular Biology 21, no. 12 (2001): 3947–58. http://dx.doi.org/10.1128/mcb.21.12.3947-3958.2001.

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ABSTRACT PTEN is a tumor suppressor that antagonizes phosphatidylinositol-3 kinase (PI3K) by dephosphorylating the D3 position of phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3). Given the importance of PTEN in regulating PtdIns-3,4,5-P3 levels, we used Affymetrix GeneChip arrays to identify genes regulated by PTEN. PTEN expression rapidly reduced the activity of Akt, which was followed by a G1 arrest and eventually apoptosis. The gene encoding insulin receptor substrate 2 (IRS-2), a mediator of insulin signaling, was found to be the most induced gene at all time points. A PI3K-specific inhibitor, LY294002, also upregulated IRS-2, providing evidence that it was the suppression of the PI3K pathway that was responsible for the message upregulation. In addition, PTEN, LY294002, and rapamycin, an inhibitor of mammalian target of rapamycin, caused a reduction in the molecular weight of IRS-2 and an increase in the association of IRS-2 with PI3K. Apparently, PTEN inhibits a negative regulator of IRS-2 to upregulate the IRS-2–PI3K interaction. These studies suggest that PtdIns-3,4,5-P3 levels regulate the specific activity and amount of IRS-2 available for insulin signaling.
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12

Hasegawa, Junya, Emi Tokuda, Takeshi Tenno, et al. "SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-binding domain." Journal of Cell Biology 193, no. 5 (2011): 901–16. http://dx.doi.org/10.1083/jcb.201012161.

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Reversible interactions between cytosolic proteins and membrane lipids such as phosphoinositides play important roles in membrane morphogenesis driven by actin polymerization. In this paper, we identify a novel lipid-binding module, which we call the SYLF domain (after the SH3YL1, Ysc84p/Lsb4p, Lsb3p, and plant FYVE proteins that contain it), that is highly conserved from bacteria to mammals. SH3YL1 (SH3 domain containing Ysc84-like 1) strongly bound to phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) and several D5-phosphorylated phosphoinositides through its SYLF domain and was localized to circular dorsal ruffles induced by platelet-derived growth factor stimulation. Interestingly, SHIP2 (the PI(3,4,5)P3 5-phosphatase, src-homology 2–containing inositol-5-phosphatase 2) was identified as a binding partner of SH3YL1, and knockdown of these proteins significantly suppressed dorsal ruffle formation. Phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), which is mainly synthesized from PI(3,4,5)P3 by the action of SHIP2, was enriched in dorsal ruffles, and PI(3,4)P2 synthesis strongly correlated with formation of the circular membrane structure. These results provide new insight into the molecular mechanism of dorsal ruffle formation and its regulation by phosphoinositide metabolism.
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13

Le, H. T., J. W. Lee, S. C. Park, et al. "Triazolium cyclodextrin click cluster–resin conjugate: an enrichment material for phosphatidylinositol (3,4,5)-triphosphate." Chemical Communications 53, no. 75 (2017): 10459–62. http://dx.doi.org/10.1039/c7cc06151j.

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14

Schlett, Katalin. "More than a mere supply of monomers: G-Actin pools regulate actin dynamics in dendritic spines." Journal of Cell Biology 216, no. 8 (2017): 2255–57. http://dx.doi.org/10.1083/jcb.201705216.

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Synaptic activity reshapes the morphology of dendritic spines via regulating F-actin arborization. In this issue, Lei et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201612042) reports a novel, G-actin–dependent regulation of actin polymerization within spine heads. They show that actin monomer levels are elevated in spines upon activity, with G-actin immobilized by the local enrichment of phosphatidylinositol (3,4,5)-triphosphate (PIP3) within the spine plasma membrane.
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15

Wu, Chongchao, Xiaofang Cui, Liyu Huang, et al. "IRTKS Promotes Insulin Signaling Transduction through Inhibiting SHIP2 Phosphatase Activity." International Journal of Molecular Sciences 20, no. 11 (2019): 2834. http://dx.doi.org/10.3390/ijms20112834.

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Insulin signaling is mediated by a highly integrated network that controls glucose metabolism, protein synthesis, cell growth, and differentiation. Our previous work indicates that the insulin receptor tyrosine kinase substrate (IRTKS), also known as BAI1-associated protein 2-like 1 (BAIAP2L1), is a novel regulator of insulin network, but the mechanism has not been fully studied. In this work we reveal that IRTKS co-localizes with Src homology (SH2) containing inositol polyphosphate 5-phosphatase-2 (SHIP2), and the SH3 domain of IRTKS directly binds to SHIP2’s catalytic domain INPP5c. IRTKS suppresses SHIP2 phosphatase to convert phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3, PIP3) to phosphatidylinositol (3,4) bisphosphate (PI(3,4)P2). IRTKS-knockout significantly increases PI(3,4)P2 level and decreases cellular PI(3,4,5)P3 content. Interestingly, the interaction between IRTKS and SHIP2 is dynamically regulated by insulin, which feeds back and affects the tyrosine phosphorylation of IRTKS. Furthermore, IRTKS overexpression elevates PIP3, activates the AKT–mTOR signaling pathway, and increases cell proliferation. Thereby, IRTKS not only associates with insulin receptors to activate PI3K but also interacts with SHIP2 to suppress its activity, leading to PIP3 accumulation and the activation of the AKT–mTOR signaling pathway to modulate cell proliferation.
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16

Miao, B., I. Skidan, J. Yang, et al. "Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains." Proceedings of the National Academy of Sciences 107, no. 46 (2010): 20126–31. http://dx.doi.org/10.1073/pnas.1004522107.

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17

Nakatsu, Fubito, Rushika M. Perera, Louise Lucast, et al. "The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics." Journal of Cell Biology 190, no. 3 (2010): 307–15. http://dx.doi.org/10.1083/jcb.201005018.

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Phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P2) and its phosphorylated product PI 3,4,5-triphosphate (PI(3,4,5)P3) are two major phosphoinositides concentrated at the plasma membrane. Their levels, which are tightly controlled by kinases, phospholipases, and phosphatases, regulate a variety of cellular functions, including clathrin-mediated endocytosis and receptor signaling. In this study, we show that the inositol 5-phosphatase SHIP2, a negative regulator of PI(3,4,5)P3-dependent signaling, also negatively regulates PI(4,5)P2 levels and is concentrated at endocytic clathrin-coated pits (CCPs) via interactions with the scaffold protein intersectin. SHIP2 is recruited early at the pits and dissociates before fission. Both knockdown of SHIP2 expression and acute production of PI(3,4,5)P3 shorten CCP lifetime by enhancing the rate of pit maturation, which is consistent with a positive role of both SHIP2 substrates, PI(4,5)P2 and PI(3,4,5)P3, on coat assembly. Because SHIP2 is a negative regulator of insulin signaling, our findings suggest the importance of the phosphoinositide metabolism at CCPs in the regulation of insulin signal output.
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18

Deuter-Reinhard, M., G. Apell, D. Pot, A. Klippel, L. T. Williams, and W. M. Kavanaugh. "SIP/SHIP inhibits Xenopus oocyte maturation induced by insulin and phosphatidylinositol 3-kinase." Molecular and Cellular Biology 17, no. 5 (1997): 2559–65. http://dx.doi.org/10.1128/mcb.17.5.2559.

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SIP (signaling inositol phosphatase) or SHIP (SH2-containing inositol phosphatase) is a recently identified SH2 domain-containing protein which has been implicated as an important signaling molecule. SIP/SHIP becomes tyrosine phosphorylated and binds the phosphotyrosine-binding domain of SHC in response to activation of hematopoietic cells. The signaling pathways and biological responses that may be regulated by SIP have not been demonstrated. SIP is a phosphatidylinositol- and inositol-polyphosphate 5-phosphatase with specificity in vitro for substrates phosphorylated at the 3' position. Phosphatidylinositol 3'-kinase (PI 3-kinase) is an enzyme which is involved in mitogenic signaling and whose phosphorylated lipid products are predicted to be substrates for SIP. We tested the hypothesis that SIP can modulate signaling by PI 3-kinase in vivo by injecting SIP cRNAs into Xenopus oocytes. SIP inhibited germinal vesicle breakdown (GVBD) induced by expression of a constitutively activated form of PI 3-kinase (p110*) and blocked GVBD induced by insulin. SIP had no effect on progesterone-induced GVBD. Catalytically inactive SIP had little effect on insulin- or PI 3-kinase-induced GVBD. Expression of SIP, but not catalytically inactive SIP, also blocked insulin-induced mitogen-activated protein kinase phosphorylation in oocytes. SIP specifically and markedly reduced the level of phosphatidylinositol (3,4,5) triphosphate [PtdIns(3,4,5)P3] generated in oocytes in response to insulin. These results demonstrate that a member of the phosphatidylinositol polyphosphate 5-phosphatase family can inhibit signaling in vivo. Further, our data suggest that the generation of PtdIns(3,4,5)P3 by PI 3-kinase is necessary for insulin-induced GVBD in Xenopus oocytes.
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19

Xie, Zhongjian, Sandra M. Chang, Sally D. Pennypacker, Er-Yuan Liao та Daniel D. Bikle. "Phosphatidylinositol-4-phosphate 5-kinase 1α Mediates Extracellular Calcium-induced Keratinocyte Differentiation". Molecular Biology of the Cell 20, № 6 (2009): 1695–704. http://dx.doi.org/10.1091/mbc.e08-07-0756.

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Extracellular calcium (Cao) is a major regulator of keratinocyte differentiation, but the mechanism is unclear. Phosphatidylinositol-4-phosphate 5-kinase 1α (PIP5K1α) is critical in synthesizing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. In this study, we sought to determine whether PIP5K1α plays a role in mediating the ability of Cao to induce keratinocyte differentiation. We found that treatment of human keratinocytes in culture with Cao resulted in increased PIP5K1α level and activity, as well as PI(4,5)P2 level, binding of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3] to and activation of phospholipase C-γ1 (PLC-γ1), with the resultant increase in inositol 1,4,5-trisphosphate (IP3) and intracellular calcium (Cai). Knockdown of PIP5K1α in human keratinocytes blocked Cao-induced increases in the binding of PI(3,4,5)P3 to PLC-γ1; PLC-γ1 activity; levels of PI(4,5)P2, IP3, and Cai; and induction of keratinocyte differentiation markers. Coimmunoprecipitation and confocal studies revealed that Cao stimulated PIP5K1α recruitment to the E-cadherin–catenin complex in the plasma membrane. Knockdown of E-cadherin or β-catenin blocked Cao-induced activation of PIP5K1α. These results indicate that after Cao stimulation PIP5K1α is recruited by the E-cadherin–catenin complex to the plasma membrane where it provides the substrate PI(4,5)P2 for both PI3K and PLC-γ1. This signaling pathway is critical for Cao-induced generation of the second messengers IP3 and Cai and keratinocyte differentiation.
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Lu, Qing, Jiang Yu, Jing Yan, Zhiyi Wei, and Mingjie Zhang. "Structural basis of the myosin X PH1N-PH2-PH1C tandem as a specific and acute cellular PI(3,4,5)P3 sensor." Molecular Biology of the Cell 22, no. 22 (2011): 4268–78. http://dx.doi.org/10.1091/mbc.e11-04-0354.

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Myosin X (MyoX) is an unconventional myosin that is known to induce the formation and elongation of filopodia in many cell types. MyoX-induced filopodial induction requires the three PH domains in its tail region, although with unknown underlying molecular mechanisms. MyoX's first PH domain is split into halves by its second PH domain. We show here that the PH1N-PH2-PH1C tandem allows MyoX to bind to phosphatidylinositol (3,4,5)-triphosphate [PI(3,4,5)P3] with high specificity and cooperativity. We further show that PH2 is responsible for the specificity of the PI(3,4,5)P3 interaction, whereas PH1 functions to enhance the lipid membrane–binding avidity of the tandem. The structure of the MyoX PH1N-PH2-PH1C tandem reveals that the split PH1, PH2, and the highly conserved interdomain linker sequences together form a rigid supramodule with two lipid-binding pockets positioned side by side for binding to phosphoinositide membrane bilayers with cooperativity. Finally, we demonstrate that disruption of PH2-mediated binding to PI(3,4,5)P3 abolishes MyoX's function in inducing filopodial formation and elongation.
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21

Taylor, Vanessa, Michelle Wong, Christian Brandts, et al. "5′ Phospholipid Phosphatase SHIP-2 Causes Protein Kinase B Inactivation and Cell Cycle Arrest in Glioblastoma Cells." Molecular and Cellular Biology 20, no. 18 (2000): 6860–71. http://dx.doi.org/10.1128/mcb.20.18.6860-6871.2000.

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ABSTRACT The tumor suppressor protein PTEN is mutated in glioblastoma multiform brain tumors, resulting in deregulated signaling through the phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB) pathway, which is critical for maintaining proliferation and survival. We have examined the relative roles of the two major phospholipid products of PI3K activity, phosphatidylinositol 3,4-biphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], in the regulation of PKB activity in glioblastoma cells containing high levels of both of these lipids due to defective PTEN expression. Reexpression of PTEN or treatment with the PI3K inhibitor LY294002 abolished the levels of both PtdIns(3,4)P2 and PtdIns(3,4,5)P3, reduced phosphorylation of PKB on Thr308 and Ser473, and inhibited PKB activity. Overexpression of SHIP-2 abolished the levels of PtdIns(3,4,5)P3, whereas PtdIns(3,4)P2 levels remained high. However, PKB phosphorylation and activity were reduced to the same extent as they were with PTEN expression. PTEN and SHIP-2 also significantly decreased the amount of PKB associated with cell membranes. Reduction of SHIP-2 levels using antisense oligonucleotides increased PKB activity. SHIP-2 became tyrosine phosphorylated following stimulation by growth factors, but this did not significantly alter its phosphatase activity or ability to antagonize PKB activation. Finally we found that SHIP-2, like PTEN, caused a potent cell cycle arrest in G1 in glioblastoma cells, which is associated with an increase in the stability of expression of the cell cycle inhibitor p27KIP1. Our results suggest that SHIP-2 plays a negative role in regulating the PI3K-PKB pathway.
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Rubashkin, Matthew G., Luke Cassereau, Russell Bainer, et al. "Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate." Cancer Research 74, no. 17 (2014): 4597–611. http://dx.doi.org/10.1158/0008-5472.can-13-3698.

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23

Shenker, Bruce J., Kathleen Boesze-Battaglia, Monika Damek Scuron, Lisa P. Walker, Ali Zekavat, and Mensur Dlakić. "The toxicity of theAggregatibacter actinomycetemcomitanscytolethal distending toxin correlates with its phosphatidylinositol-3,4,5-triphosphate phosphatase activity." Cellular Microbiology 18, no. 2 (2015): 223–43. http://dx.doi.org/10.1111/cmi.12497.

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24

Park, Hee-Won, Yufeng Tong, Wolfram Tempel, et al. "P4-119: Crystal Structures of Apo Centaurin Alpha1 and its Complex With Phosphatidylinositol 3,4,5-triphosphate." Alzheimer's & Dementia 6 (July 2010): e57-e57. http://dx.doi.org/10.1016/j.jalz.2010.08.178.

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Mitsushima, Masaru, Fumiko Toyoshima, and Eisuke Nishida. "Dual Role of Cdc42 in Spindle Orientation Control of Adherent Cells." Molecular and Cellular Biology 29, no. 10 (2009): 2816–27. http://dx.doi.org/10.1128/mcb.01713-08.

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ABSTRACT The spindle orientation is regulated by the interaction of astral microtubules with the cell cortex. We have previously shown that spindles in nonpolarized adherent cells are oriented parallel to the substratum by an actin cytoskeleton- and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]-dependent mechanism. Here, we show that Cdc42, a Rho family of small GTPases, has an essential role in this mechanism of spindle orientation by regulating both the actin cytoskeleton and PtdIns(3,4,5)P3. Knockdown of Cdc42 suppresses PI(3)K activity in M phase and induces spindle misorientation. Moreover, knockdown of Cdc42 disrupts the cortical actin structures in metaphase cells. Our results show that p21-activated kinase 2 (PAK2), a target of Cdc42 and/or Rac1, plays a key role in regulating actin reorganization and spindle orientation downstream from Cdc42. Surprisingly, PAK2 regulates spindle orientation in a kinase activity-independent manner. βPix, a guanine nucleotide exchange factor for Rac1 and Cdc42, is shown to mediate this kinase-independent function of PAK2. This study thus demonstrates that spindle orientation in adherent cells is regulated by two distinct pathways downstream from Cdc42 and uncovers a novel role of the Cdc42-PAK2-βPix-actin pathway for this mechanism.
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Mitra, Prasenjit, Yingjie Zhang, Lucia E. Rameh, et al. "A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast." Journal of Cell Biology 166, no. 2 (2004): 205–11. http://dx.doi.org/10.1083/jcb.200404150.

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The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.
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Shenker, Bruce J., Kathleen Boesze-Battaglia, Ali Zekavat, Lisa Walker, Dave Besack, and Hydar Ali. "Inhibition of mast cell degranulation by a chimeric toxin containing a novel phosphatidylinositol-3,4,5-triphosphate phosphatase." Molecular Immunology 48, no. 1-3 (2010): 203–10. http://dx.doi.org/10.1016/j.molimm.2010.08.009.

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Wong, Chuu-Yun A., Hada Wuriyanghan, Yan Xie, Ming-Fong Lin, Peter W. Abel, and Yaping Tu. "Epigenetic Regulation of Phosphatidylinositol 3,4,5-Triphosphate-dependent Rac Exchanger 1 Gene Expression in Prostate Cancer Cells." Journal of Biological Chemistry 286, no. 29 (2011): 25813–22. http://dx.doi.org/10.1074/jbc.m110.211292.

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van Hooren, K. W. E. M., D. van Breevoort, M. Fernandez-Borja, et al. "Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 regulates epinephrine-induced exocytosis of Weibel-Palade bodies." Journal of Thrombosis and Haemostasis 12, no. 2 (2014): 273–81. http://dx.doi.org/10.1111/jth.12460.

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Morimura, Shigeru, Katsuo Suzuki, and Kazuhide Takahashi. "Nonmuscle myosin IIA is required for lamellipodia formation through binding to WAVE2 and phosphatidylinositol 3,4,5-triphosphate." Biochemical and Biophysical Research Communications 404, no. 3 (2011): 834–40. http://dx.doi.org/10.1016/j.bbrc.2010.12.069.

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Yang, Lingzhi, Takeaki Ozawa, Haifeng Dong, and Xueji Zhang. "Optogenetic Control of Phosphatidylinositol (3,4,5)‐Triphosphate Production by Light‐Sensitive Cryptochrome Proteins on the Plasma Membrane." Chinese Journal of Chemistry 39, no. 5 (2021): 1240–46. http://dx.doi.org/10.1002/cjoc.202000648.

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32

Kortholt, Arjan, Jason S. King, Ineke Keizer-Gunnink, Adrian J. Harwood, and Peter J. M. Van Haastert. "Phospholipase C Regulation of Phosphatidylinositol 3,4,5-trisphosphate-mediated Chemotaxis." Molecular Biology of the Cell 18, no. 12 (2007): 4772–79. http://dx.doi.org/10.1091/mbc.e07-05-0407.

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Generation of a phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] gradient within the plasma membrane is important for cell polarization and chemotaxis in many eukaryotic cells. The gradient is produced by the combined activity of phosphatidylinositol 3-kinase (PI3K) to increase PI(3,4,5)P3 on the membrane nearest the polarizing signal and PI(3,4,5)P3 dephosphorylation by phosphatase and tensin homolog deleted on chromosome ten (PTEN) elsewhere. Common to both of these enzymes is the lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which is not only the substrate of PI3K and product of PTEN but also important for membrane binding of PTEN. Consequently, regulation of phospholipase C (PLC) activity, which hydrolyzes PI(4,5)P2, could have important consequences for PI(3,4,5)P3 localization. We investigate the role of PLC in PI(3,4,5)P3-mediated chemotaxis in Dictyostelium. plc-null cells are resistant to the PI3K inhibitor LY294002 and produce little PI(3,4,5)P3 after cAMP stimulation, as monitored by the PI(3,4,5)P3-specific pleckstrin homology (PH)-domain of CRAC (PHCRACGFP). In contrast, PLC overexpression elevates PI(3,4,5)P3 and impairs chemotaxis in a similar way to loss of pten. PI3K localization at the leading edge of plc-null cells is unaltered, but dissociation of PTEN from the membrane is strongly reduced in both gradient and uniform stimulation with cAMP. These results indicate that local activation of PLC can control PTEN localization and suggest a novel mechanism to regulate the internal PI(3,4,5)P3 gradient.
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Moeller, Lars C., Xia Cao, Alexandra M. Dumitrescu, Hisao Seo та Samuel Refetoff. "Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor β through the phosphatidylinositol 3-kinase pathway". Nuclear Receptor Signaling 4, № 1 (2006): nrs.04020. http://dx.doi.org/10.1621/nrs.04020.

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Thyroid hormone (TH) action is mediated principally through binding of the hormone ligand, 3,3,5-triiodothyronine (T3), to TH receptors (TRs). This hormone-receptor interaction recruits other proteins to form complexes that regulate gene expression by binding to DNA sequences in the promoter of target genes. We recently described an extranuclear mechanism of TH action that consists of the association of TH-liganded TRβ with p85α [regulatory subunit of phosphatidylinositol 3-kinase (PI3K)] in the cytosol and subsequent activation of the PI3K, generating phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. This initiates the activation of a signaling cascade by phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its substrate p70S6K, leading to the stimulation of ZAKI-4α synthesis, a calcineurin inhibitor. Furthermore, we found that this same mechanism leads to induction of the transcription factor hypoxia-inducible factor (HIF-1α), and its target genes, glucose transporter (GLUT)1, platelet-type phosphofructokinase (PFKP), and monocarboxylate transporter (MCT) 4. These genes are of special interest, because their products have important roles in cellular glucose metabolism, from glucose uptake (GLUT1) to glycolysis (PFKP) and lactate export (MCT4). These results demonstrate that the TH-TRβ complex can exert a non-genomic action in the cytosol leading to changes in gene expression by direct (HIF-1α) and indirect (ZAKI-4α, GLUT1, PFKP) means.
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Jun, Hyun Sik, Young Mok Lee, Ki Duk Song, Brian C. Mansfield, and Janice Y. Chou. "G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis." Blood 117, no. 14 (2011): 3881–92. http://dx.doi.org/10.1182/blood-2010-08-302059.

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Abstract G6PC3 (or glucose-6-phosphatase-β) deficiency underlies a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. Here we show that murine G6pc3−/− neutrophils undergoing ER stress activate protein kinase-like ER kinase and phosphatidylinositol 3,4,5-trisphosphate/Akt signaling pathways, and that neutrophil apoptosis is mediated in part by the intrinsic mitochondrial pathway. In G6PC3-deficient patients, granulocyte colony-stimulating factor (G-CSF) improves neutropenia, but its impact on neutrophil apoptosis and dysfunction is unknown. We now show that G-CSF delays neutrophil apoptosis in vitro by modulating apoptotic mediators. However, G6pc3−/− neutrophils in culture exhibit accelerated apoptosis compared with wild-type neutrophils both in the presence or absence of G-CSF. Limiting glucose (0.6mM) accelerates apoptosis but is more pronounced for wild-type neutrophils, leading to similar survival profiles for both neutrophil populations. In vivo G-CSF therapy completely corrects neutropenia and normalizes levels of p-Akt, phosphatidylinositol 3,4,5-trisphosphate, and active caspase-3. Neutrophils from in vivo G-CSF–treated G6pc3−/− mice exhibit increased glucose uptake and elevated intracellular levels of G6P, lactate, and adenosine-5′-triphosphate, leading to improved functionality. Together, the results strongly suggest that G-CSF improves G6pc3−/− neutrophil survival by modulating apoptotic mediators and rectifies function by enhancing energy homeostasis.
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Paunovska, Kalina, Alejandro Da Silva Sanchez, Matthew T. Foster, et al. "Increased PIP3 activity blocks nanoparticle mRNA delivery." Science Advances 6, no. 30 (2020): eaba5672. http://dx.doi.org/10.1126/sciadv.aba5672.

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The biological pathways that affect drug delivery in vivo remain poorly understood. We hypothesized that altering cell metabolism with phosphatidylinositol (3,4,5)-triphosphate (PIP3), a bioactive lipid upstream of the metabolic pathway PI3K (phosphatidylinositol 3-kinase)/AKT/ mTOR (mammalian target of rapamycin) would transiently increase protein translated by nanoparticle-delivered messenger RNA (mRNA) since these pathways increase growth and proliferation. Instead, we found that PIP3 blocked delivery of clinically-relevant lipid nanoparticles (LNPs) across multiple cell types in vitro and in vivo. PIP3-driven reductions in LNP delivery were not caused by toxicity, cell uptake, or endosomal escape. Interestingly, RNA sequencing and metabolomics analyses suggested an increase in basal metabolic rate. Higher transcriptional activity and mitochondrial expansion led us to formulate two competing hypotheses that explain the reductions in LNP-mediated mRNA delivery. First, PIP3 induced consumption of limited cellular resources, “drowning out” exogenously-delivered mRNA. Second, PIP3 triggers a catabolic response that leads to protein degradation and decreased translation.
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36

Kunisaki, Yuya, Akihiko Nishikimi, Yoshihiko Tanaka, et al. "DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis." Journal of Cell Biology 174, no. 5 (2006): 647–52. http://dx.doi.org/10.1083/jcb.200602142.

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Neutrophils are highly motile leukocytes, and they play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. We show that DOCK2, which is a mammalian homologue of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, regulates motility and polarity during neutrophil chemotaxis. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP3) at the leading edge. On the other hand, we found that DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K)–dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP3-dependent membrane translocation and Rac activation.
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Noh, Eun-Mi, Jinny Park, Hwa-Ryung Song, et al. "Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6354261.

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Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.
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38

Mentel, Matthias, Vibor Laketa, Devaraj Subramanian, Hartmut Gillandt, and Carsten Schultz. "Photoaktivierbares und zellmembranpermeables Phosphatidylinositol-3,4,5-trisphosphat." Angewandte Chemie 123, no. 16 (2011): 3895–98. http://dx.doi.org/10.1002/ange.201007796.

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39

Watanabe, Yutaka, Hajimu Hirofuji, and Shoichiro Ozaki. "Synthesis of a Phosphatidylinositol 3,4,5-Trisphosphate." Tetrahedron Letters 35, no. 1 (1994): 123–24. http://dx.doi.org/10.1016/0040-4039(94)88179-0.

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40

Sason, Hagit, Michal Milgrom, Aryeh M. Weiss, et al. "EnteropathogenicEscherichia coliSubverts Phosphatidylinositol 4,5-Bisphosphate and Phosphatidylinositol 3,4,5-Trisphosphate upon Epithelial Cell Infection." Molecular Biology of the Cell 20, no. 1 (2009): 544–55. http://dx.doi.org/10.1091/mbc.e08-05-0516.

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Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] are phosphoinositides (PIs) present in small amounts in the inner leaflet of the plasma membrane (PM) lipid bilayer of host target cells. They are thought to modulate the activity of proteins involved in enteropathogenic Escherichia coli (EPEC) infection. However, the role of PI(4,5)P2and PI(3,4,5)P3in EPEC pathogenesis remains obscure. Here we show that EPEC induces a transient PI(4,5)P2accumulation at bacterial infection sites. Simultaneous actin accumulation, likely involved in the construction of the actin-rich pedestal, is also observed at these sites. Acute PI(4,5)P2depletion partially diminishes EPEC adherence to the cell surface and actin pedestal formation. These findings are consistent with a bimodal role, whereby PI(4,5)P2contributes to EPEC association with the cell surface and to the maximal induction of actin pedestals. Finally, we show that EPEC induces PI(3,4,5)P3clustering at bacterial infection sites, in a translocated intimin receptor (Tir)-dependent manner. Tir phosphorylated on tyrosine 454, but not on tyrosine 474, forms complexes with an active phosphatidylinositol 3-kinase (PI3K), suggesting that PI3K recruited by Tir prompts the production of PI(3,4,5)P3beneath EPEC attachment sites. The functional significance of this event may be related to the ability of EPEC to modulate cell death and innate immunity.
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41

Brauweiler, Anne, Idan Tamir, Joseph Dal Porto, et al. "Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain–Containing 5′ Inositol Phosphatase (Ship)." Journal of Experimental Medicine 191, no. 9 (2000): 1545–54. http://dx.doi.org/10.1084/jem.191.9.1545.

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Although the Src homology 2 domain–containing 5′ inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P3) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P3 signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.
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42

Sasaki, T., J. Sasaki, K. Watanabe, and A. Suzuki. "Non-invasive visualization of the lipid product of class I PI3K in transgenic mouse models." Biochemical Society Transactions 35, no. 2 (2007): 215–18. http://dx.doi.org/10.1042/bst0350215.

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PI3Ks (phosphoinositide 3-kinases) regulate many critical cellular responses by producing PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate). To facilitate the spatio-temporal characterization of PI(3,4,5)P3 in living primary cells, we generated a novel strain of transgenic mice [AktPH (Akt pleckstrin homology domain)–GFP (green fluorescent protein) Tg (transgenic) mice] that express a fluorescent bioprobe for PI(3,4,5)P3/PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate). By crossing AktPH–GFP Tg mice with strains of gene-targeted ‘knockout’ mice lacking a particular phosphoinositide-metabolizing enzyme, we have been able to evaluate the contribution of each enzyme to PI(3,4,5)P3 localization in migrating neutrophils. Our results indicate that PI3Kγ and the PI(3,4,5)P3 phosphatase SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1] are the key regulators of PI(3,4,5)P3 dynamics during fMet-Leu-Phe (N-formylmethionyl-leucylphenylalanine; ‘chemotactic peptide’)-stimulated neutrophil migration. Our study has also validated the fluorescent transgenic strategy for studying PI(3,4,5)P3 metabolism in physiological and pathological situations.
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43

Atala, Anthony. "Re: Epigenetic Regulation of Phosphatidylinositol 3,4,5-Triphosphate-Dependent Rac Exchanger 1 Gene Expression in Prostate Cancer Cells." Journal of Urology 187, no. 3 (2012): 1127–28. http://dx.doi.org/10.1016/j.juro.2011.11.022.

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44

Ijuin, T., and T. Takenawa. "Regulation of Insulin Signaling by the Phosphatidylinositol 3,4,5-Triphosphate Phosphatase SKIP through the Scaffolding Function of Pak1." Molecular and Cellular Biology 32, no. 17 (2012): 3570–84. http://dx.doi.org/10.1128/mcb.00636-12.

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45

Takahashi, Kazuhide, and Katsuo Suzuki. "WAVE2 targeting to phosphatidylinositol 3,4,5-triphosphate mediated by insulin receptor substrate p53 through a complex with WAVE2." Cellular Signalling 22, no. 11 (2010): 1708–16. http://dx.doi.org/10.1016/j.cellsig.2010.06.011.

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46

DOWLER, Simon, Richard A. CURRIE, David G. CAMPBELL, et al. "Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities." Biochemical Journal 351, no. 1 (2000): 19–31. http://dx.doi.org/10.1042/bj3510019.

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The second messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is generated by the action of phosphoinositide 3-kinase (PI 3-kinase), and regulates a plethora of cellular processes. An approach for dissecting the mechanisms by which these processes are regulated is to identify proteins that interact specifically with PtdIns(3,4,5)P3. The pleckstrin homology (PH) domain has become recognized as the specialized module used by many proteins to interact with PtdIns(3,4,5)P3. Recent work has led to the identification of a putative phosphatidylinositol 3,4,5-trisphosphate-binding motif (PPBM) at the N-terminal regions of PH domains that interact with this lipid. We have searched expressed sequence tag databases for novel proteins containing PH domains possessing a PPBM. Surprisingly, many of the PH domains that we identified do not bind PtdIns(3,4,5)P3, but instead possess unexpected and novel phosphoinositide-binding specificitiesin vitro. These include proteins possessing PH domains that interact specifically with PtdIns(3,4)P2 [TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns4P [FAPP1 (phosphatidylinositol-four-phosphate adaptor protein-1)], PtdIns3P [PEPP1 (phosphatidylinositol-three-phosphate-binding PH-domain protein-1) and AtPH1] and PtdIns(3,5)P2 (centaurin-β2). We have also identified two related homologues of PEPP1, termed PEPP2 and PEPP3, that may also interact with PtdIns3P. This study lays the foundation for future work to establish the phospholipid-binding specificities of these proteins in vivo, and their physiological role(s).
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47

Kamen, Lynn A., Jonathan Levinsohn, and Joel A. Swanson. "Differential Association of Phosphatidylinositol 3-Kinase, SHIP-1, and PTEN with Forming Phagosomes." Molecular Biology of the Cell 18, no. 7 (2007): 2463–72. http://dx.doi.org/10.1091/mbc.e07-01-0061.

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In macrophages, enzymes that synthesize or hydrolyze phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] regulate Fcγ receptor-mediated phagocytosis. Inhibition of phosphatidylinositol 3-kinase (PI3K) or overexpression of the lipid phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP-1), which hydrolyze PI(3,4,5)P3 to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], respectively, inhibit phagocytosis in macrophages. To examine how these enzymes regulate phagosome formation, the distributions of yellow fluorescent protein (YFP) chimeras of enzymes and pleckstrin homology (PH) domains specific for their substrates and products were analyzed quantitatively. PTEN-YFP did not localize to phagosomes, suggesting that PTEN regulates phagocytosis globally within the macrophage. SHIP1-YFP and p85-YFP were recruited to forming phagosomes. SHIP1-YFP sequestered to the leading edge and dissociated from phagocytic cups earlier than did p85-cyan fluorescent protein, indicating that SHIP-1 inhibitory activities are restricted to the early stages of phagocytosis. PH domain chimeras indicated that early during phagocytosis, PI(3,4,5)P3 was slightly more abundant than PI(3,4)P2 at the leading edge of the forming cup. These results support a model in which phagosomal PI3K generates PI(3,4,5)P3 necessary for later stages of phagocytosis, PTEN determines whether those late stages can occur, and SHIP-1 regulates when and where they occur by transiently suppressing PI(3,4,5)P3-dependent activities necessary for completion of phagocytosis.
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48

Keum, Dongil, Martin Kruse, Dong-Il Kim, Bertil Hille, and Byung-Chang Suh. "Phosphoinositide 5- and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence." Proceedings of the National Academy of Sciences 113, no. 26 (2016): E3686—E3695. http://dx.doi.org/10.1073/pnas.1606472113.

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Voltage-sensing phosphatases (VSPs) are homologs of phosphatase and tensin homolog (PTEN), a phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] 3-phosphatase. However, VSPs have a wider range of substrates, cleaving 3-phosphate from PI(3,4)P2 and probably PI(3,4,5)P3 as well as 5-phosphate from phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and PI(3,4,5)P3 in response to membrane depolarization. Recent proposals say these reactions have differing voltage dependence. Using Förster resonance energy transfer probes specific for different PIs in living cells with zebrafish VSP, we quantitate both voltage-dependent 5- and 3-phosphatase subreactions against endogenous substrates. These activities become apparent with different voltage thresholds, voltage sensitivities, and catalytic rates. As an analytical tool, we refine a kinetic model that includes the endogenous pools of phosphoinositides, endogenous phosphatase and kinase reactions connecting them, and four exogenous voltage-dependent 5- and 3-phosphatase subreactions of VSP. We show that apparent voltage threshold differences for seeing effects of the 5- and 3-phosphatase activities in cells are not due to different intrinsic voltage dependence of these reactions. Rather, the reactions have a common voltage dependence, and apparent differences arise only because each VSP subreaction has a different absolute catalytic rate that begins to surpass the respective endogenous enzyme activities at different voltages. For zebrafish VSP, our modeling revealed that 3-phosphatase activity against PI(3,4,5)P3 is 55-fold slower than 5-phosphatase activity against PI(4,5)P2; thus, PI(4,5)P2 generated more slowly from dephosphorylating PI(3,4,5)P3 might never accumulate. When 5-phosphatase activity was counteracted by coexpression of a phosphatidylinositol 4-phosphate 5-kinase, there was accumulation of PI(4,5)P2 in parallel to PI(3,4,5)P3 dephosphorylation, emphasizing that VSPs can cleave the 3-phosphate of PI(3,4,5)P3.
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49

Rodrigues, Gerard A., Marco Falasca, Zhongtao Zhang, Siew Hwa Ong, and Joseph Schlessinger. "A Novel Positive Feedback Loop Mediated by the Docking Protein Gab1 and Phosphatidylinositol 3-Kinase in Epidermal Growth Factor Receptor Signaling." Molecular and Cellular Biology 20, no. 4 (2000): 1448–59. http://dx.doi.org/10.1128/mcb.20.4.1448-1459.2000.

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ABSTRACT The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR) we tested the ability of Gab1 to associate with and modulate signaling by this receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that overexpression of Gab1 potentiates EGF-induced activation of the mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via the EGFR. The PH domain of Gab1 was shown to bind specifically to phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3 kinase, and is required for activation of Gab1-mediated enhancement of EGFR signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma membrane in response to EGF and is required for efficient tyrosine phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1 PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR.
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Carter, A. N., R. Huang, A. Sorisky, C. P. Downes, and S. E. Rittenhouse. "Phosphatidylinositol 3,4,5-trisphosphate is formed from phosphatidylinositol 4,5-bisphosphate in thrombin-stimulated platelets." Biochemical Journal 301, no. 2 (1994): 415–20. http://dx.doi.org/10.1042/bj3010415.

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Platelets accumulate PtdIns(3,4,5)P3 and PtdIns(3,4)P2 in response to thrombin and thrombin-receptor-directed peptide in a GTP-dependent manner. These phosphoinositides are considered to be mediators of signaling events in a variety of cells. We have examined the metabolic route by which PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are synthesized by briefly (10 min) incubating platelets with high activities of [32P]Pi, followed by 20 or 60 s exposure to thrombin, and analysing the relative radioactivities of the individual phosphate groups in the resulting labelled PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The phosphate group possessing the highest specific activity under such non-equilibrium labelling conditions indicates the last one added in a metabolic sequence. The thrombin-stimulated rate of labelling of PtdIns(3,4)P2 was significantly slower than that of PtdIns(3,4,5)P3. Increased labelled PtdIns3P was not detected within 60 s. The measured relative radioactivities decreased in the order 3 > 5 > 4 >> 1 for PtdIns(3,4,5)P3 and 3 > 4 >> 1 for PtdIns(3,4)P2. On the basis of the results of both rate-of-labelling and specific radioactivity analyses we conclude that PtdIns(3,4,5)Pa is formed by 3-OH phosphorylation of PtdIns(4,5)P2, whereas PtdIns(3,4)P2, may be formed by 3-OH phosphorylation of PtdIns4P and/or dephosphorylation of PtdIns(3,4,5)P3. These findings point to the activation of phosphoinositide 3-kinase as a critical receptor-regulated step in thrombin-stimulated platelets.
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