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Cited by 156PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingMetabolism, Diabetes, and Cancer

Beyond PI3Ks: targeting phosphoinositide kinases in disease

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Burke, John E., Triscott, Joanna, Emerling, Brooke M., Hammond, Gerald R. V.·2023·Nature Reviews Drug Discovery
DOI 10.1038/s41573-022-00582-5PMC PMC9663198
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Abstract

Lipid phosphoinositides are master regulators of almost all aspects of a cell's life and death and are generated by the tightly regulated activity of phosphoinositide kinases. Although extensive efforts have focused on drugging class I phosphoinositide 3-kinases (PI3Ks), recent years have revealed opportunities for targeting almost all phosphoinositide kinases in human diseases, including cancer, immunodeficiencies, viral infection and neurodegenerative disease. This has led to widespread efforts in the clinical development of potent and selective inhibitors of phosphoinositide kinases. This Review summarizes our current understanding of the molecular basis for the involvement of phosphoinositide kinases in disease and assesses the preclinical and clinical development of phosphoinositide kinase inhibitors.

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  • Lysosomes are critical for apoptosis in two ways: lysosomal membrane permeabilization releases hydrolases into cytosol; dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse with lysosomes, and be digested by lysosomal enzymes.

    “Lysosomes are critical for apoptosis in two ways. In the cell undergoing apoptosis, the lysosomal membrane is permeabilized in a controlled fashion, allowing the release of lysosomal hydrolases into the cytosol.23 To complete the process, the dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse24,25with their lysosomes, and then be digested and cleared by lysos”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [23]

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  1. [1]Balla T Phosphoinositides: tiny lipids with giant impact on cell regulation Physiol. Rev. 2013 93 1019 1137 10.1152/physrev.00028.2012 23899561 PMC3962547 · DOI · Paper page
  2. [2]Dickson EJ Hille B Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids Biochem. J. 2019 476 1 23 10.1042/BCJ20180022 30617162 PMC6342281 · DOI · Paper page
  3. [4]Hasegawa J Strunk BS Weisman LS PI5P and PI(3,5)P2: minor, but essential phosphoinositides Cell Struct. Funct. 2017 42 49 60 10.1247/csf.17003 28302928 PMC5846621 · DOI
  4. [5]Gozzelino L De Santis MC Gulluni F Hirsch E Martini M PI(3,4)P2 signaling in cancer and metabolism Front. Oncol. 2020 10 360 10.3389/fonc.2020.00360 32296634 PMC7136497 · DOI
  5. [6]Batrouni AG Baskin JM The chemistry and biology of phosphatidylinositol 4-phosphate at the plasma membrane Bioorg. Med. Chem. 2021 40 116190 10.1016/j.bmc.2021.116190 33965837 PMC8169619 · DOI
  6. [7]Hammond GRV Burke JE Novel roles of phosphoinositides in signaling, lipid transport, and disease Curr. Opin. Cell Biol. 2020 63 57 67 10.1016/j.ceb.2019.12.007 31972475 PMC7247936 · DOI · Paper page
  7. [8]Baba T Balla T Emerging roles of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate as regulators of multiple steps in autophagy J. Biochem. 2020 168 329 336 10.1093/jb/mvaa089 32745205 PMC7778341 · DOI
  8. [9]Vanhaesebroeck B Perry MWD Brown JR André F Okkenhaug K PI3K inhibitors are finally coming of age Nat. Rev. Drug Discov. 2021 20 741 769 10.1038/s41573-021-00209-1 34127844 PMC9297732 · DOI
  9. [10]Vasan N Cantley LC At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy Nat. Rev. Clin. Oncol. 2022 19 471 485 10.1038/s41571-022-00633-1 35484287 PMC11215755 · DOI
  10. [11]Li J PI-273, a substrate-competitive, specific small molecule inhibitor of PI4KIIα, inhibits the growth of breast cancer cells Cancer Res. 2017 77 6253 6266 10.1158/0008-5472.CAN-17-0484 28827373 · DOI
  11. [12]Sengupta N A large scale high-throughput screen identifies chemical inhibitors of phosphatidylinositol 4-kinase type II alpha J. Lipid Res. 2019 60 683 693 10.1194/jlr.D090159 30626625 PMC6399489 · DOI
  12. [13]Zolov SN In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P Proc. Natl Acad. Sci. USA 2012 109 17472 17477 10.1073/pnas.1203106109 23047693 PMC3491506 · DOI
  13. [14]Giridharan SSP Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes eLife 2022 11 e69709 10.7554/eLife.69709 35040777 PMC8816382 · DOI
  14. [15]Rutherford AC The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport J. Cell Sci. 2006 119 3944 3957 10.1242/jcs.03153 16954148 PMC1904490 · DOI
  15. [16]Cabezas A Pattni K Stenmark H Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1 Gene 2006 371 34 41 10.1016/j.gene.2005.11.009 16448788 · DOI
  16. [17]Dong X PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome Nat. Commun. 2010 1 38 10.1038/ncomms1037 20802798 PMC2928581 · DOI
  17. [18]de Lartigue J PIKfyve regulation of endosome-linked pathways Traffic 2009 10 883 893 10.1111/j.1600-0854.2009.00915.x 19582903 PMC2723830 · DOI
  18. [19]Oppelt A Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration EMBO Rep. 2013 14 57 64 10.1038/embor.2012.183 23154468 PMC3537138 · DOI
  19. [20]Bissig C Hurbain I Raposo G van Niel G PIKfyve activity regulates reformation of terminal storage lysosomes from endolysosomes Traffic 2017 18 747 757 10.1111/tra.12525 28857423 · DOI
  20. [21]Choy CH Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence J. Cell Sci. 2018 131 jcs213587 10.1242/jcs.213587 29661845 PMC6031331 · DOI
  21. [22]Sbrissa D Ikonomov OC Shisheva A Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization J. Biol. Chem. 2002 277 6073 6079 10.1074/jbc.M110194200 11706043 · DOI
  22. [23]Shisheva A Sbrissa D Ikonomov O Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells Mol. Cell Biol. 1999 19 623 634 10.1128/MCB.19.1.623 9858586 PMC83920 · DOI
  23. [24]Sbrissa D Ikonomov OC Shisheva A PIKfyve lipid kinase is a protein kinase: downregulation of 5′-phosphoinositide product formation by autophosphorylation Biochemistry 2000 39 15980 15989 10.1021/bi001897f 11123925 · DOI
  24. [25]Ikonomov OC The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve−/− embryos but normality of PIKfyve+/− mice J. Biol. Chem. 2011 286 13404 13413 10.1074/jbc.M111.222364 21349843 PMC3075686 · DOI · Paper page
  25. [26]Takasuga S Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine Proc. Natl Acad. Sci. USA 2013 110 1726 1731 10.1073/pnas.1213212110 23322734 PMC3562790 · DOI
  26. [27]Jin N VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse EMBO J. 2008 27 3221 3234 10.1038/emboj.2008.248 19037259 PMC2600653 · DOI
  27. [28]Sbrissa D A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity Mol. Cell Biol. 2004 24 10437 10447 10.1128/MCB.24.23.10437-10447.2004 15542851 PMC529046 · DOI
  28. [29]Sbrissa D Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex J. Biol. Chem. 2007 282 23878 23891 10.1074/jbc.M611678200 17556371 · DOI
  29. [30]Duex JE Tang F Weisman LS The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover J. Cell Biol. 2006 172 693 704 10.1083/jcb.200512105 16492811 PMC2063702 · DOI
  30. [31]Rudge SA Anderson DM Emr SD Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase Mol. Biol. Cell 2004 15 24 36 10.1091/mbc.e03-05-0297 14528018 PMC307524 · DOI
  31. [32]Zhang Y Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice Proc. Natl Acad. Sci. USA 2007 104 17518 17523 10.1073/pnas.0702275104 17956977 PMC2077288 · DOI
  32. [33]Chow CY Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J Nature 2007 448 68 72 10.1038/nature05876 17572665 PMC2271033 · DOI
  33. [34]Lenk GM Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J PLoS Genet. 2011 7 e1002104 10.1371/journal.pgen.1002104 21655088 PMC3107197 · DOI
  34. [35]Chow CY Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS Am. J. Hum. Genet. 2009 84 85 88 10.1016/j.ajhg.2008.12.010 19118816 PMC2668033 · DOI · Paper page
  35. [36]Zhang X Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration Brain 2008 131 1990 2001 10.1093/brain/awn114 18556664 PMC2724900 · DOI
  36. [37]Lenk GM Biallelic mutations of VAC14 in pediatric-onset neurological disease Am. J. Hum. Genet. 2016 99 188 194 10.1016/j.ajhg.2016.05.008 27292112 PMC5005439 · DOI
  37. [38]Lees JA Li P Kumar N Weisman LS Reinisch KM Insights into lysosomal PI(3,5)P2 homeostasis from a structural-biochemical analysis of the PIKfyve lipid kinase complex Mol. Cell 2020 80 736 743.e4 10.1016/j.molcel.2020.10.003 33098764 PMC7962480 · DOI
  38. [39]Hayakawa M Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors Bioorg. Med. Chem. 2006 14 6847 6858 10.1016/j.bmc.2006.06.046 16837202 · DOI
  39. [40]Jefferies HBJ A selective PIKfyve inhibitor blocks PtdIns(3,5)P2 production and disrupts endomembrane transport and retroviral budding EMBO Rep. 2008 9 164 170 10.1038/sj.embor.7401155 18188180 PMC2246419 · DOI
  40. [41]Wada Y Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor Blood 2007 109 1156 1164 10.1182/blood-2006-04-019398 17053051 · DOI
  41. [42]Cai X PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling Chem. Biol. 2013 20 912 921 10.1016/j.chembiol.2013.05.010 23890009 PMC4878021 · DOI
  42. [43]Hayakawa N Structure-activity relationship study, target identification, and pharmacological characterization of a small molecular IL-12/23 inhibitor, APY0201 Bioorg. Med. Chem. 2014 22 3021 3029 10.1016/j.bmc.2014.03.036 24767819 · DOI
  43. [44]Sharma G A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis Autophagy 2019 15 1694 1718 10.1080/15548627.2019.1586257 30806145 PMC6735543 · DOI
  44. [45]Trabbic CJ Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity J. Med. Chem. 2015 58 2489 2512 10.1021/jm501997q 25654321 PMC4360382 · DOI
  45. [46]Cho H Indolyl-pyridinyl-propenone-induced methuosis through the inhibition of PIKFYVE ACS Omega 2018 3 6097 6103 10.1021/acsomega.8b00202 30221232 PMC6130785 · DOI
  46. [47]Hudkins RL Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent J. Med. Chem. 2012 55 903 913 10.1021/jm201449n 22148921 · DOI
  47. [48]Qiao Y Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer Nat. Cancer 2021 2 978 993 10.1038/s43018-021-00237-1 34738088 PMC8562569 · DOI
  48. [49]Guerrero-Valero M Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy Proc. Natl Acad. Sci. USA 2021 118 e2009469118 10.1073/pnas.2009469118 33653949 PMC7958260 · DOI
  49. [50]Sawade L Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth Nat. Commun. 2020 11 2835 10.1038/s41467-020-16696-6 32503983 PMC7275063 · DOI
  50. [51]Soto C Pritzkow S Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases Nat. Neurosci. 2018 21 1332 1340 10.1038/s41593-018-0235-9 30250260 PMC6432913 · DOI · Paper page
  51. [52]Soares AC PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding J. Biol. Chem. 2021 296 100636 10.1016/j.jbc.2021.100636 33831417 PMC8134070 · DOI
  52. [54]See, S. K. et al. PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation. Preprint available at bioRxiv10.1101/2021.01.21.427704 (2021).
  53. [55]Shi Y Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons Nat. Med. 2018 24 313 325 10.1038/nm.4490 29400714 PMC6112156 · DOI · Paper page
  54. [56]Lenk GM Cerebral hypomyelination associated with biallelic variants of FIG4 Hum. Mutat. 2019 40 619 630 10.1002/humu.23720 30740813 PMC6467804 · DOI
  55. [57]Lakkaraju AKK Loss of PIKfyve drives the spongiform degeneration in prion diseases EMBO Mol. Med. 2021 13 e14714 10.15252/emmm.202114714 34291577 PMC8518562 · DOI
  56. [58]Carette JE Ebola virus entry requires the cholesterol transporter Niemann–Pick C1 Nature 2011 477 340 343 10.1038/nature10348 21866103 PMC3175325 · DOI
  57. [59]Nelson EA The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection PLoS Negl. Trop. Dis. 2017 11 e0005540 10.1371/journal.pntd.0005540 28403145 PMC5402990 · DOI
  58. [60]Qiu S Ebola virus requires phosphatidylinositol (3,5) bisphosphate production for efficient viral entry Virology 2018 513 17 28 10.1016/j.virol.2017.09.028 29031163 · DOI
  59. [61]Kang Y-L Inhibition of PIKfyve kinase prevents infection by Zaire Ebolavirus and SARS-CoV-2 Proc. Natl Acad. Sci. USA 2020 117 20803 20813 10.1073/pnas.2007837117 32764148 PMC7456157 · DOI
  60. [62]Ou X Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV Nat. Commun. 2020 11 1620 10.1038/s41467-020-15562-9 32221306 PMC7100515 · DOI · Paper page
  61. [63]Riva L Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing Nature 2020 586 113 119 10.1038/s41586-020-2577-1 32707573 PMC7603405 · DOI
  62. [64]Bouhaddou M The global phosphorylation landscape of SARS-CoV-2 Infection Cell 2020 182 685 712.e19 10.1016/j.cell.2020.06.034 32645325 PMC7321036 · DOI
  63. [65]Dayam RM The lipid kinase PIKfyve coordinates the neutrophil immune response through the activation of the Rac GTPase J. Immunol. 2017 199 2096 2105 10.4049/jimmunol.1601466 28779020 · DOI
  64. [66]Gayle S Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma Blood 2017 129 1768 1778 10.1182/blood-2016-09-736892 28104689 PMC5766845 · DOI
  65. [67]de Campos CB Identification of PIKfyve kinase as a target in multiple myeloma Haematologica 2020 105 1641 1649 10.3324/haematol.2019.222729 31582538 PMC7271606 · DOI
  66. [68]Milan E Fabbri M Cenci S Autophagy in plasma cell ontogeny and malignancy J. Clin. Immunol. 2016 36 Suppl. 1 18 24 10.1007/s10875-016-0254-9 26984755 PMC4891390 · DOI
  67. [69]Hou J-Z Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy Oncol. Rep. 2019 41 1971 1979 30569119
  68. [70]Loijens JC Boronenkov IV Parker GJ Anderson RA The phosphatidylinositol 4-phosphate 5-kinase family Adv. Enzym. Regul. 1996 36 115 140 10.1016/0065-2571(95)00005-4 8869744 · DOI
  69. [71]Rameh LE Tolias KF Duckworth BC Cantley LC A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate Nature 1997 390 192 196 10.1038/36621 9367159 · DOI
  70. [72]Bazenet CE Ruano AR Brockman JL Anderson RA The human erythrocyte contains two forms of phosphatidylinositol-4-phosphate 5-kinase which are differentially active toward membranes J. Biol. Chem. 1990 265 18012 18022 10.1016/S0021-9258(18)38264-4 2170402 · DOI
  71. [73]Ling LE Schulz JT Cantley LC Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells J. Biol. Chem. 1989 264 5080 5088 10.1016/S0021-9258(18)83702-4 2538472 · DOI
  72. [74]Lundquist MR Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy Mol. Cell 2018 70 531 544.e9 10.1016/j.molcel.2018.03.037 29727621 PMC5991623 · DOI
  73. [75]Hu A PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis J. Lipid Res. 2018 59 507 514 10.1194/jlr.M082149 29353240 PMC5832930 · DOI
  74. [76]Ishihara H Cloning of cDNAs encoding two isoforms of 68-kDa type I phosphatidylinositol-4-phosphate 5-kinase J. Biol. Chem. 1996 271 23611 23614 10.1074/jbc.271.39.23611 8798574 · DOI
  75. [77]Loijens JC Anderson RA Type I phosphatidylinositol-4-phosphate 5-kinases are distinct members of this novel lipid kinase family J. Biol. Chem. 1996 271 32937 32943 10.1074/jbc.271.51.32937 8955136 · DOI
  76. [78]Oude Weernink PA Schmidt M Jakobs KH Regulation and cellular roles of phosphoinositide 5-kinases Eur. J. Pharmacol. 2004 500 87 99 10.1016/j.ejphar.2004.07.014 15464023 · DOI
  77. [79]van den Bout I Divecha N PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions J. Cell. Sci. 2009 122 3837 3850 10.1242/jcs.056127 19889969 · DOI
  78. [80]Rao VD Misra S Boronenkov IV Anderson RA Hurley JH Structure of type II beta phosphatidylinositol phosphate kinase: a protein kinase fold flattened for interfacial phosphorylation Cell 1998 94 829 839 10.1016/S0092-8674(00)81741-9 9753329 · DOI
  79. [81]Clarke JH Irvine RF The activity, evolution and association of phosphatidylinositol 5-phosphate 4-kinases Adv. Biol. Regul. 2012 52 40 45 10.1016/j.advenzreg.2011.09.002 21945524 · DOI
  80. [82]Emerling BM Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors Cell 2013 155 844 857 10.1016/j.cell.2013.09.057 24209622 PMC4070383 · DOI
  81. [83]Shim H Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system Proc. Natl Acad. Sci. USA 2016 113 7596 7601 10.1073/pnas.1600934113 27313209 PMC4941458 · DOI
  82. [84]Lamia KA Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase beta-/- mice Mol. Cell Biol. 2004 24 5080 5087 10.1128/MCB.24.11.5080-5087.2004 15143198 PMC416424 · DOI
  83. [85]Clarke JH Irvine RF Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization Biochem. J. 2013 454 49 57 10.1042/BJ20130488 23758345 PMC3749867 · DOI
  84. [86]Bulley SJ In B cells, phosphatidylinositol 5-phosphate 4-kinase-α synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling Proc. Natl Acad. Sci. USA 2016 113 10571 10576 10.1073/pnas.1522478113 27601656 PMC5035885 · DOI
  85. [87]Sumita K The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis Mol. Cell 2016 61 187 198 10.1016/j.molcel.2015.12.011 26774281 PMC4747657 · DOI
  86. [88]Bultsma Y Keune W-J Divecha N PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha Biochem. J. 2010 430 223 235 10.1042/BJ20100341 20583997 · DOI
  87. [89]Jones DR Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta Mol. Cell 2006 23 685 695 10.1016/j.molcel.2006.07.014 16949365 · DOI
  88. [90]Keune W-J Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress Sci. Signal. 2012 5 ra86 10.1126/scisignal.2003223 23193159 · DOI
  89. [91]Mackey AM Sarkes DA Bettencourt I Asara JM Rameh LE PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation Sci. Signal. 2014 7 ra104 ra104 10.1126/scisignal.2005191 25372051 PMC4579097 · DOI
  90. [92]Semenas J The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer Proc. Natl Acad. Sci. USA 2014 111 E3689 E3698 10.1073/pnas.1405801111 25071204 PMC4156761 · DOI
  91. [93]Wright BD The lipid kinase PIP5K1C regulates pain signaling and sensitization Neuron 2014 82 836 847 10.1016/j.neuron.2014.04.006 24853942 PMC4074510 · DOI
  92. [94]Andrews DM Identification and optimization of a novel series of selective PIP5K inhibitors Bioorg. Med. Chem. 2022 54 116557 10.1016/j.bmc.2021.116557 34922306 · DOI
  93. [95]Sarwar M The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor Oncogene 2019 38 375 389 10.1038/s41388-018-0438-2 30104711 PMC6336681 · DOI
  94. [96]Adhikari H Counter CM Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability Nat. Commun. 2018 9 3646 10.1038/s41467-018-05692-6 30194290 PMC6128905 · DOI
  95. [97]Choi S Chen M Cryns VL Anderson RA A nuclear phosphoinositide kinase complex regulates p53 Nat. Cell Biol. 2019 21 462 475 10.1038/s41556-019-0297-2 30886346 PMC7017954 · DOI · Paper page
  96. [98]Muscolini M Phosphatidylinositol 4-phosphate 5-kinase α activation critically contributes to CD28-dependent signaling responses J. Immunol. 2013 190 5279 5286 10.4049/jimmunol.1203157 23589613 · DOI
  97. [99]Muscolini M Phosphatidylinositol 4-phosphate 5-kinase α and Vav1 mutual cooperation in CD28-mediated actin remodeling and signaling functions J. Immunol. 2015 194 1323 1333 10.4049/jimmunol.1401643 25539813 · DOI
  98. [100]Camperio C CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes Immunol. Lett. 2014 158 134 142 10.1016/j.imlet.2013.12.020 24412596 · DOI
  99. [101]Chen S Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells Proc. Natl Acad. Sci. USA 2021 118 e2002486118 10.1073/pnas.2002486118 34001596 PMC8166193 · DOI
  100. [102]Ravi A PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay Dev. Cell 2021 56 1661 1676.e10 10.1016/j.devcel.2021.04.019 33984270 PMC9012263 · DOI
  101. [103]Kitagawa M Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality Nat. Commun. 2017 8 2200 10.1038/s41467-017-02287-5 29259156 PMC5736559 · DOI
  102. [104]Sivakumaren SC Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors Cell Chem. Biol. 2020 27 525 537.e6 10.1016/j.chembiol.2020.02.003 32130941 PMC7286548 · DOI
  103. [105]Manz TD Discovery and structure-activity relationship study of (Z)-5-methylenethiazolidin-4-one derivatives as potent and selective Pan-phosphatidylinositol 5-phosphate 4-kinase inhibitors J. Med. Chem. 2020 63 4880 4895 10.1021/acs.jmedchem.0c00227 32298120 PMC7292230 · DOI
  104. [106]Davis MI A homogeneous, high-throughput assay for phosphatidylinositol 5-phosphate 4-kinase with a novel, rapid substrate preparation PLoS ONE 2013 8 e54127 10.1371/journal.pone.0054127 23326584 PMC3542272 · DOI
  105. [107]Wortmann L Discovery and characterization of the potent and highly selective 1,7-naphthyridine-based inhibitors BAY-091 and BAY-297 of the kinase PIP4K2A J. Med. Chem. 2021 64 15883 15911 10.1021/acs.jmedchem.1c01245 34699202 · DOI
  106. [108]Voss MD Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta Biochem. Biophys. Res. Commun. 2014 449 327 331 10.1016/j.bbrc.2014.05.024 24845568 · DOI
  107. [109]Clarke JH The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site Biochem. J. 2015 466 359 367 10.1042/BJ20141333 25495341 PMC4687057 · DOI
  108. [110]Al-Ramahi I Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein eLife 2017 6 e29123 10.7554/eLife.29123 29256861 PMC5743427 · DOI
  109. [111]Manz TD Structure-activity relationship study of covalent Pan-phosphatidylinositol 5-phosphate 4-kinase inhibitors ACS Med. Chem. Lett. 2020 11 346 352 10.1021/acsmedchemlett.9b00402 32184968 PMC7074221 · DOI
  110. [112]See CS Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) Eur. J. Med. Chem. 2018 156 344 367 10.1016/j.ejmech.2018.07.011 30015072 · DOI
  111. [113]Boffey HK Development of selective phosphatidylinositol 5-phosphate 4-kinase γ inhibitors with a non-ATP-competitive, allosteric binding mode J. Med. Chem. 2022 65 3359 3370 10.1021/acs.jmedchem.1c01819 35148092 PMC9097471 · DOI
  112. [114]Arora GK Palamiuc L Emerling BM Expanding role of PI5P4Ks in cancer: a promising druggable target FEBS Lett. 2022 596 3 16 10.1002/1873-3468.14237 34822164 PMC9154051 · DOI
  113. [115]Luoh S-W Venkatesan N Tripathi R Overexpression of the amplified Pip4k2beta gene from 17q11-12 in breast cancer cells confers proliferation advantage Oncogene 2004 23 1354 1363 10.1038/sj.onc.1207251 14691457 · DOI
  114. [116]Keune W-J Low PIP4K2B expression in human breast tumors correlates with reduced patient survival: a role for PIP4K2B in the regulation of E-cadherin expression Cancer Res. 2013 73 6913 6925 10.1158/0008-5472.CAN-13-0424 24127122 PMC5321494 · DOI
  115. [117]Lima K PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia Cancer Genet. 2019 233–234 56 66 10.1016/j.cancergen.2019.04.002 31109595 · DOI
  116. [118]Jude JG A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival Oncogene 2015 34 1253 1262 10.1038/onc.2014.77 24681948 PMC4130659 · DOI
  117. [119]Shin YJ PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma J. Exp. Med. 2019 216 1120 1134 10.1084/jem.20172170 30898893 PMC6504209 · DOI
  118. [120]Wang DG PIP4Ks suppress insulin signaling through a catalytic-independent mechanism Cell Rep. 2019 27 1991 2001.e5 10.1016/j.celrep.2019.04.070 31091439 PMC6619495 · DOI
  119. [122]Poli A PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity Proc. Natl Acad. Sci. USA 2021 118 e2010053118 10.1073/pnas.2010053118 34312224 PMC8346797 · DOI
  120. [123]He Z The PIP5K2A gene and schizophrenia in the Chinese population-a case-control study Schizophr. Res. 2007 94 359 365 10.1016/j.schres.2007.04.013 17555944 · DOI
  121. [124]Thiselton DL Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS) Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 153B 323 331 19475563 PMC4011176
  122. [125]Schwab SG Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia Mol. Psychiatry 2006 11 837 846 10.1038/sj.mp.4001864 16801950 · DOI
  123. [126]Noch EK Yim I Milner TA Cantley LC Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain J. Comp. Neurol. 2021 529 434 449 10.1002/cne.24956 32449185 PMC7683367 · DOI
  124. [127]Balla T Isolation and molecular cloning of wortmannin-sensitive bovine type III phosphatidylinositol 4-kinases J. Biol. Chem. 1997 272 18358 18366 10.1074/jbc.272.29.18358 9218477 · DOI
  125. [128]Boura E Nencka R Phosphatidylinositol 4-kinases: function, structure, and inhibition Exp. Cell Res. 2015 337 136 145 10.1016/j.yexcr.2015.03.028 26183104 · DOI
  126. [129]Dornan GL McPhail JA Burke JE Type III phosphatidylinositol 4 kinases: structure, function, regulation, signalling and involvement in disease Biochemical Soc. Trans. 2016 44 260 266 10.1042/BST20150219 26862213 · DOI
  127. [130]Tan J Brill JA Cinderella story: PI4P goes from precursor to key signaling molecule Crit. Rev. Biochem. Mol. Biol. 2014 49 33 58 10.3109/10409238.2013.853024 24219382 · DOI
  128. [132]Nakatsu F PtdIns4P synthesis by PI4KIIIα at the plasma membrane and its impact on plasma membrane identity J. Cell Biol. 2012 199 1003 1016 10.1083/jcb.201206095 23229899 PMC3518224 · DOI · Paper page
  129. [133]Bojjireddy N Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels J. Biol. Chem. 2014 289 6120 6132 10.1074/jbc.M113.531426 24415756 PMC3937678 · DOI
  130. [134]Nakagawa T Goto K Kondo H Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase J. Biol. Chem. 1996 271 12088 12094 10.1074/jbc.271.20.12088 8662589 · DOI
  131. [135]Lees JA Architecture of the human PI4KIIIα lipid kinase complex Proc. Natl Acad. Sci. USA 2017 114 13720 13725 10.1073/pnas.1718471115 29229838 PMC5748228 · DOI
  132. [136]Wu X Structural insights into assembly and regulation of the plasma membrane phosphatidylinositol 4-kinase complex Dev. Cell 2014 28 19 29 10.1016/j.devcel.2013.11.012 24360784 PMC4349574 · DOI
  133. [137]Baskin JM The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane Nat. Cell Biol. 2016 18 132 138 10.1038/ncb3271 26571211 PMC4689616 · DOI
  134. [138]Raghu P Joseph A Krishnan H Singh P Saha S Phosphoinositides: regulators of nervous system function in health and disease Front. Mol. Neurosci. 2019 12 208 10.3389/fnmol.2019.00208 31507376 PMC6716428 · DOI
  135. [139]Pagnamenta AT Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis Hum. Mol. Genet. 2015 24 3732 3741 10.1093/hmg/ddv117 25855803 PMC4459391 · DOI
  136. [140]Salter CG Biallelic PI4KA variants cause neurological, intestinal and immunological disease Brain 2021 144 3597 3610 10.1093/brain/awab313 34415310 PMC8719846 · DOI
  137. [141]Bigorgne AE TTC7A mutations disrupt intestinal epithelial apicobasal polarity J. Clin. Invest. 2014 124 328 337 10.1172/JCI71471 24292712 PMC3871247 · DOI
  138. [142]Avitzur Y Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease Gastroenterology 2014 146 1028 1039 10.1053/j.gastro.2014.01.015 24417819 PMC4002656 · DOI
  139. [143]Chen R Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias J. Allergy Clin. Immunol. 2013 132 656 664.e17 10.1016/j.jaci.2013.06.013 23830146 PMC3759618 · DOI
  140. [144]Berger KL Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication Proc. Natl Acad. Sci. USA 2009 106 7577 7582 10.1073/pnas.0902693106 19376974 PMC2678598 · DOI
  141. [145]Dorobantu CM Modulation of the host lipid landscape to promote RNA virus replication: the picornavirus encephalomyocarditis virus converges on the pathway used by hepatitis C virus PLoS Pathog. 2015 11 e1005185 10.1371/journal.ppat.1005185 26406250 PMC4583462 · DOI
  142. [146]Burke JE Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors Science 2014 344 1035 1038 10.1126/science.1253397 24876499 PMC4046302 · DOI
  143. [147]McPhail JA Ottosen EH Jenkins ML Burke JE The molecular basis of Aichi virus 3A protein activation of phosphatidylinositol 4 kinase IIIβ, PI4KB, through ACBD3 Structure 2017 25 121 131 10.1016/j.str.2016.11.016 27989622 · DOI
  144. [148]Klima M Structural insights and in vitro reconstitution of membrane targeting and activation of human PI4KB by the ACBD3 protein Sci. Rep. 2016 6 23641 10.1038/srep23641 27009356 PMC4806292 · DOI
  145. [149]Hausser A Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex Nat. Cell Biol. 2005 7 880 886 10.1038/ncb1289 16100512 PMC1458033 · DOI
  146. [150]Chalupská D Phosphatidylinositol 4-kinase IIIβ (PI4KB) forms highly flexible heterocomplexes that include ACBD3, 14-3-3, and Rab11 proteins Sci. Rep. 2019 9 567 10.1038/s41598-018-37158-6 30679637 PMC6345845 · DOI
  147. [151]McPhail JA Characterization of the c10orf76-PI4KB complex and its necessity for Golgi PI4P levels and enterovirus replication EMBO Rep. 2020 21 e48441 10.15252/embr.201948441 31829496 PMC7001497 · DOI
  148. [152]Mesmin B Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP EMBO J. 2017 36 3156 3174 10.15252/embj.201796687 28978670 PMC5666618 · DOI
  149. [153]Brill JA Hime GR Scharer-Schuksz M Fuller MT A phospholipid kinase regulates actin organization and intercellular bridge formation during germline cytokinesis Development 2000 127 3855 3864 10.1242/dev.127.17.3855 10934029 · DOI
  150. [154]Baba T Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function Proc. Natl Acad. Sci. USA 2020 117 28102 28113 10.1073/pnas.2007432117 33106410 PMC7668188 · DOI
  151. [155]van der Schaar HM Dorobantu CM Albulescu L Strating JRPM van Kuppeveld FJM Fat(al) attraction: picornaviruses usurp lipid transfer at membrane contact sites to create replication organelles Trends Microbiol. 2016 24 535 546 10.1016/j.tim.2016.02.017 27020598 PMC7126954 · DOI
  152. [156]Altan-Bonnet N Balla T Phosphatidylinositol 4-kinases: hostages harnessed to build panviral replication platforms Trends Biochem. Sci. 2012 37 293 302 10.1016/j.tibs.2012.03.004 22633842 PMC3389303 · DOI
  153. [157]Hsu N-Y Viral reorganization of the secretory pathway generates distinct organelles for RNA replication Cell 2010 141 799 811 10.1016/j.cell.2010.03.050 20510927 PMC2982146 · DOI
  154. [158]Nakanishi S Catt KJ Balla T A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids Proc. Natl Acad. Sci. USA 1995 92 5317 5321 10.1073/pnas.92.12.5317 7777504 PMC41685 · DOI
  155. [159]Nakanishi S Catt KJ Balla T A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids Proc. Natl Acad. Sci. USA 1995 92 5317 5321 10.1073/pnas.92.12.5317 7777504 PMC41685 · DOI
  156. [160]Meyers R Cantley LC Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase J. Biol. Chem. 1997 272 4384 4390 10.1074/jbc.272.7.4384 9020160 · DOI
  157. [161]Bianco A Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity PLoS Pathog. 2012 8 e1002576 10.1371/journal.ppat.1002576 22412376 PMC3297592 · DOI
  158. [162]Vaillancourt FH Evaluation of phosphatidylinositol-4-kinase IIIα as a hepatitis C virus drug target J. Virol. 2012 86 11595 11607 10.1128/JVI.01320-12 22896614 PMC3486294 · DOI
  159. [163]Leivers AL Discovery of selective small molecule type III phosphatidylinositol 4-kinase alpha (PI4KIIIα) inhibitors as anti hepatitis C (HCV) agents J. Med. Chem. 2014 57 2091 2106 10.1021/jm400781h 23944386 · DOI
  160. [164]Raubo P Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα) Bioorg. Med. Chem. Lett. 2015 25 3189 3193 10.1016/j.bmcl.2015.05.093 26087940 · DOI
  161. [165]Waring MJ Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation Chem. Commun. 2014 50 5388 5390 10.1039/C3CC48391F 24366037 · DOI
  162. [166]Knight Z A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling Cell 2006 125 733 747 10.1016/j.cell.2006.03.035 16647110 PMC2946820 · DOI · Paper page
  163. [167]Rutaganira FU Design and structural characterization of potent and selective inhibitors of phosphatidylinositol 4 kinase IIIβ J. Med. Chem. 2016 59 1830 1839 10.1021/acs.jmedchem.5b01311 26885694 PMC5289284 · DOI
  164. [168]Phillpotts RJ Wallace J Tyrrell DA Tagart VB Therapeutic activity of enviroxime against rhinovirus infection in volunteers Antimicrob. Agents Chemother. 1983 23 671 675 10.1128/AAC.23.5.671 6870216 PMC184785 · DOI
  165. [169]Arita M Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity J. Virol. 2011 85 2364 2372 10.1128/JVI.02249-10 21177810 PMC3067798 · DOI
  166. [170]van der Schaar HM A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ Antimicrob. Agents Chemother. 2013 57 4971 4981 10.1128/AAC.01175-13 23896472 PMC3811463 · DOI
  167. [171]Mejdrová I Highly selective phosphatidylinositol 4-Kinase IIIβ inhibitors and structural insight into their mode of action J. Med. Chem. 2015 58 3767 3793 10.1021/acs.jmedchem.5b00499 25897704 · DOI
  168. [172]Mejdrová I Rational design of novel highly potent and selective phosphatidylinositol 4-Kinase IIIβ (PI4KB) inhibitors as broad-spectrum antiviral agents and tools for chemical biology J. Med. Chem. 2017 60 100 118 10.1021/acs.jmedchem.6b01465 28004945 · DOI
  169. [173]McPhail JA Burke JE Molecular mechanisms of PI4K regulation and their involvement in viral replication Traffic 2022 10.1111/tra.12841 35579216 · DOI
  170. [174]Lamarche MJ Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4-kinase beta inhibitors Antimicrob. Agents Chemother. 2012 56 5149 5156 10.1128/AAC.00946-12 22825118 PMC3457382 · DOI
  171. [175]Reuberson J Discovery of a potent, orally bioavailable PI4KIIIβ inhibitor (UCB9608) able to significantly prolong allogeneic organ engraftment in vivo J. Med. Chem. 2018 61 6705 6723 10.1021/acs.jmedchem.8b00521 29952567 · DOI
  172. [176]Spickler C Phosphatidylinositol 4-kinase III beta is essential for replication of human rhinovirus and its inhibition causes a lethal phenotype in vivo Antimicrob. Agents Chemother. 2013 57 3358 3368 10.1128/AAC.00303-13 23650168 PMC3697394 · DOI
  173. [177]McNamara CW Targeting Plasmodium PI(4)K to eliminate malaria Nature 2013 504 248 253 10.1038/nature12782 24284631 PMC3940870 · DOI
  174. [178]Manjunatha UH A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis Nature 2017 546 376 380 10.1038/nature22337 28562588 PMC5473467 · DOI
  175. [179]Ghidelli-Disse S Identification of Plasmodium PI4 kinase as target of MMV390048 by chemoproteomics Malar. J. 2014 13 P38 10.1186/1475-2875-13-S1-P38 · DOI
  176. [180]Kato N Diversity-oriented synthesis yields novel multistage antimalarial inhibitors Nature 2016 538 344 349 10.1038/nature19804 27602946 PMC5515376 · DOI
  177. [181]Paquet T Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase Sci. Transl. Med. 2017 9 eaad9735 10.1126/scitranslmed.aad9735 28446690 PMC5731459 · DOI
  178. [182]Fienberg S Structural basis for inhibitor potency and selectivity of Plasmodium falciparum phosphatidylinositol 4-kinase inhibitors ACS Infect. Dis. 2020 6 3048 3063 10.1021/acsinfecdis.0c00566 32966036 · DOI
  179. [183]Arendse LB Wyllie S Chibale K Gilbert IH Plasmodium kinases as potential drug targets for malaria: challenges and opportunities ACS Infect. Dis. 2021 7 518 534 10.1021/acsinfecdis.0c00724 33590753 PMC7961706 · DOI
  180. [184]Brunschwig C UCT943, a next-generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria Antimicrob. Agents Chemother. 2018 62 62 PMC6125526 29941635
  181. [185]Adhikari H Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity Nat. Commun. 2021 12 5248 10.1038/s41467-021-25523-5 34504076 PMC8429657 · DOI
  182. [186]Kattan WE Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer Proc. Natl Acad. Sci. USA 2021 118 e2114126118 10.1073/pnas.2114126118 34903667 PMC8713765 · DOI
  183. [187]Shi L Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3-amplified lung adenocarcinoma cells Proc. Natl Acad. Sci. USA 2021 118 e2023537118 10.1073/pnas.2023537118 34155143 PMC8237628 · DOI
  184. [188]Tan X PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma Sci. Transl. Med. 2020 12 eaax3772 10.1126/scitranslmed.aax3772 31969487 PMC7702266 · DOI · Paper page
  185. [189]Gupta S Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice Cell 2007 129 957 968 10.1016/j.cell.2007.03.051 17540175 · DOI
  186. [190]Gulluni F De Santis MC Margaria JP Martini M Hirsch E Class II PI3K functions in cell biology and disease Trends Cell Biol. 2019 29 339 359 10.1016/j.tcb.2019.01.001 30691999 · DOI
  187. [191]Lo W-T Structural basis of phosphatidylinositol 3-kinase C2α function Nat. Struct. Mol. Biol. 2022 29 218 228 10.1038/s41594-022-00730-w 35256802 PMC8930771 · DOI
  188. [192]Gaidarov I Smith ME Domin J Keen JH The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking Mol. Cell 2001 7 443 449 10.1016/S1097-2765(01)00191-5 11239472 · DOI
  189. [193]Wang H Autoregulation of class II Alpha PI3K activity by its lipid-binding PX-C2 domain module Mol. Cell 2018 71 343 351.e4 10.1016/j.molcel.2018.06.042 30029007 · DOI
  190. [194]Chen K-E Tillu VA Chandra M Collins BM Molecular basis for membrane recruitment by the PX and C2 domains of class II phosphoinositide 3-kinase-C2α Structure 2018 26 1612 1625.e4 10.1016/j.str.2018.08.010 30293811 · DOI
  191. [195]Posor Y Spatiotemporal control of endocytosis by phosphatidylinositol-3, 4-bisphosphate Nature 2013 499 233 237 10.1038/nature12360 23823722 · DOI
  192. [196]Yoshioka K Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function Nat. Med. 2012 18 1560 1569 10.1038/nm.2928 22983395 · DOI
  193. [197]Franco I PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function Dev. Cell 2014 28 647 658 10.1016/j.devcel.2014.01.022 24697898 PMC4042153 · DOI
  194. [198]Alliouachene S Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice Diabetologia 2016 59 1503 1512 10.1007/s00125-016-3963-y 27138914 PMC4901096 · DOI
  195. [199]Boukhalfa A PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress Nat. Commun. 2020 11 294 10.1038/s41467-019-14086-1 31941925 PMC6962367 · DOI
  196. [200]Tiosano D Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction PLoS Genet. 2019 15 e1008088 10.1371/journal.pgen.1008088 31034465 PMC6508738 · DOI
  197. [201]Gulluni F PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation Science 2021 374 eabk0410 10.1126/science.abk0410 34882480 PMC7612254 · DOI
  198. [202]Alliouachene S Inactivation of the class II PI3K-C2β potentiates insulin signaling and sensitivity Cell Rep. 2015 13 1881 1894 10.1016/j.celrep.2015.10.052 26655903 PMC4675724 · DOI
  199. [203]Anquetil T PI3KC2β inactivation stabilizes VE-cadherin junctions and preserves vascular integrity EMBO Rep. 2021 22 e51299 10.15252/embr.202051299 33880878 PMC8183416 · DOI
  200. [204]Posor Y Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover Dev. Cell 2022 57 1694 1711.e7 10.1016/j.devcel.2022.06.011 35809565 PMC7613278 · DOI

200 of 280 shown

Authors
Burke, J. E., Triscott, J., Emerling, B. M., & Hammond, G. R. V.
Affiliations
  • University of British Columbia (CA)
  • University of Bern (CH)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • University of Pittsburgh (US)
Corresponding author
  • Burke, John E.
  • Emerling, Brooke M.
  • Hammond, Gerald R. V.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2022-11-14
Volume
22
Issue
5
Pages
357-386
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-022-00582-5
PMC
PMC9663198
OpenAlex
W4308949853
Cited by
156
References
292
Citations by year
2026: 43 · 2025: 58 · 2024: 31 · 2023: 23 · 2022: 1
FWCI
2.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
Funders
  • National Science Foundation (75N91019D00024)
  • Cancer Research Society (17686, CRS-843232, 843232)
  • Michael Smith Health Research BC (2020-04241, 17686)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (168998, 207635, 310030)
  • National Institutes of Health (R03TR003624)
  • Canadian Institutes of Health Research (168998, 2020-04241)
  • Natural Sciences and Engineering Research Council of Canada (rgpin-2020-04241, 2020-04241)
  • National Cancer Institute (75N91019D00024, R01CA237536, 75N91020F00003)
  • National Institute of General Medical Sciences (R01GM143583, R35GM119412)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
phosphoinositide kinases, phosphatidylinositol 3-kinase, cancer, immunodeficiency, viral infection, neurodegenerative diseases, small-molecule kinase inhibitors, drug development
MeSH terms
Humans, Neoplasms, Phosphatidylinositols, Virus Diseases, Neurodegenerative Diseases, Phosphatidylinositol 3-Kinases

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