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Wikipedia

PIKFYVE

December 15, 2023

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.[5][6]

PIKFYVE
Identifiers
AliasesPIKFYVE, CFD, FAB1, HEL37, PIP5K, PIP5K3, ZFYVE29, phosphoinositide kinase, FYVE-type zinc finger containing
External IDsOMIM: 609414 MGI: 1335106 HomoloGene: 32115 GeneCards: PIKFYVE
Orthologs
SpeciesHumanMouse
Entrez

200576

18711

Ensembl

ENSG00000115020

ENSMUSG00000025949

UniProt

Q9Y2I7

Q9Z1T6

RefSeq (mRNA)

NM_001002881
NM_001178000
NM_015040
NM_152671

NM_011086
NM_001310624

RefSeq (protein)

NP_001171471
NP_055855
NP_689884

NP_001297553
NP_035216

Location (UCSC)Chr 2: 208.27 – 208.36 MbChr 1: 65.23 – 65.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function edit

The principal enzymatic activity of PIKfyve is to phosphorylate PtdIns3P to PtdIns(3,5)P2. PIKfyve activity is responsible for the production of both PtdIns(3,5)P2 and phosphatidylinositol 5-phosphate (PtdIns5P).[7][8][9][10] PIKfyve is a large protein, containing a number of functional domains and expressed in several spliced forms. The reported full-length mouse and human cDNA clones encode proteins of 2052 and 2098 amino acid residues, respectively.[6][11][12][13] By directly binding membrane PtdIns(3)P,[14] the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes.[6][14] Impaired PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes lysosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis and impaired lysosome fission process and homeostasis.[15] Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of vesicular dynamics,[16][17] thereby affecting a number of trafficking pathways that emanate from or traverse the endosomal system en route to the trans-Golgi network or later compartments along the endocytic pathway.[18][19][20][21][22][23]

Medical significance edit

PIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois-Neetens corneal fleck dystrophy.[24] Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre-implantation embryo.[25] PIKfyve’s role in pathogen invasion is deduced by evidence from cell studies implicating PIKfyve activity in HIV and Salmonella replication.[21][26][27] A link of PIKfyve with type 2 diabetes is inferred by the observations that PIKfyve perturbation inhibits insulin-regulated glucose uptake.[28][29] Concordantly, mice with selective Pikfyve gene disruption in skeletal muscle, the tissue mainly responsible for the decrease of postprandial blood sugar, exhibit systemic insulin resistance; glucose intolerance; hyperinsulinemia; and increased adiposity, i.e. symptoms, typical for human prediabetes.[30]

PIKfyve inhibitors as potential therapeutics in Cancer edit

Several small molecule PIKfyve inhibitors have shown promise as cancer therapeutics in preclinical studies due to selective toxicity in non-Hodgkin lymphoma B cells [31] or in U-251 glioblastoma cells. [32] PIKfyve inhibitors cause cell death also in A-375 melanoma cells, which depend on autophagy for growth and proliferation, due to impaired lysosome homeostasis. [33] The potential therapeutic use of PIKfyve inhibitors awaits clinical trials.

Interactions edit

PIKfyve physically associates with its regulator ArPIKfyve, a protein encoded by the human gene VAC14, and the Sac1 domain-containing PtdIns(3,5)P2 5-phosphatase Sac3, encoded by FIG4, to form a stable ternary heterooligomeric complex that is scaffolded by ArPIKfyve homooligomeric interactions. The presence of two enzymes with opposing activities for PtdIns(3,5)P2 synthesis and turnover in a single complex indicates the requirement for a tight control of PtdIns(3,5)P2 levels.[17][34][35] PIKfyve also interacts with the Rab9 effector RABEPK and the kinesin adaptor JLP, encoded by SPAG9.[19][23] These interactions link PIKfyve to microtubule-based endosome to trans-Golgi network traffic. Under sustained activation of glutamate receptors PIKfyve binds to and facilitates the lysosomal degradation of Cav1.2, voltage-dependent calcium channel type 1.2, thereby protecting the neurons from excitotoxicity.[36] PIKfyve negatively regulates Ca2+-dependent exocytosis in neuroendocrine cells without affecting voltage-gated calcium channels.[37]

Evolutionary biology edit

PIKFYVE belongs to a large family of evolutionarily-conserved lipid kinases. Single copy genes, encoding similarly-structured FYVE-domain–containing phosphoinositide kinases exist in most genomes from yeast to man. The plant A. thaliana has several copies of the enzyme. Higher eukaryotes (after D. melanogaster), acquire an additional DEP domain. The S. cerevisiae enzyme Fab1p is required for PtdIns(3,5)P2 synthesis under basal conditions and in response to hyperosmotic shock. PtdIns5P, made by PIKfyve kinase activity in mammalian cells, is not detected in budding yeast.[38] Yeast Fab1p associates with Vac14p (the ortholog of human ArPIKfyve) and Fig4p (the ortholog of Sac3).[39] The yeast Fab1 complex also includes Vac7p and probably Atg18p, proteins that are not detected in the mammalian PIKfyve complex.[40] S. cerevisiae could survive without Fab1.[41] In contrast, the knockout of the FYVE domain-containing enzymes in A. thaliana, D. melanogaster, C. elegans and M. musculus leads to embryonic lethality indicating that the FYVE-domain–containing phosphoinositide kinases have become essential in embryonic development of multicellular organisms.[25][42][43][44] Thus, in evolution, the FYVE-domain-containing phosphoinositide kinases retain several aspects of the structural organization, enzyme activity and protein interactions from budding yeast. In higher eukaryotes, the enzymes acquire one additional domain, a role in the production of PtdIns5P, a new set of interacting proteins and become essential in embryonic development.

References edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000115020 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025949 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: Phosphoinositide kinase, FYVE finger containing".
  6. ^ a b c Shisheva A, Sbrissa D, Ikonomov O (January 1999). "Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells". Molecular and Cellular Biology. 19 (1): 623–34. doi:10.1128/MCB.19.1.623. PMC 83920. PMID 9858586.
  7. ^ Shisheva A (2001). "PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2)". Cell Biology International. 25 (12): 1201–6. doi:10.1006/cbir.2001.0803. PMID 11748912. S2CID 29411107.
  8. ^ Sbrissa D, Ikonomov OC, Deeb R, Shisheva A (December 2002). "Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells". The Journal of Biological Chemistry. 277 (49): 47276–84. doi:10.1074/jbc.M207576200. PMID 12270933.
  9. ^ Sbrissa D, Ikonomov OC, Filios C, Delvecchio K, Shisheva A (August 2012). "Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636". American Journal of Physiology. Cell Physiology. 303 (4): C436-46. doi:10.1152/ajpcell.00105.2012. PMC 3422984. PMID 22621786.
  10. ^ Zolov SN, Bridges D, Zhang Y, Lee WW, Riehle E, Verma R, et al. (October 2012). "In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P". Proceedings of the National Academy of Sciences of the United States of America. 109 (43): 17472–7. Bibcode:2012PNAS..10917472Z. doi:10.1073/pnas.1203106109. PMC 3491506. PMID 23047693.
  11. ^ Sbrissa D, Ikonomov OC, Shisheva A (July 1999). "PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin". The Journal of Biological Chemistry. 274 (31): 21589–97. doi:10.1074/jbc.274.31.21589. PMID 10419465.
  12. ^ Sbrissa D, Ikonomov OC, Deeb R, Shisheva A (December 2002). "Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells". The Journal of Biological Chemistry. 277 (49): 47276–84. doi:10.1074/jbc.M207576200. PMID 12270933.
  13. ^ Cabezas A, Pattni K, Stenmark H (April 2006). "Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1". Gene. 371 (1): 34–41. doi:10.1016/j.gene.2005.11.009. PMID 16448788.
  14. ^ a b Sbrissa D, Ikonomov OC, Shisheva A (February 2002). "Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization". The Journal of Biological Chemistry. 277 (8): 6073–9. doi:10.1074/jbc.M110194200. PMID 11706043.
  15. ^ Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, et al. (February 2019). "A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis". Autophagy. 15 (10): 1694–1718. doi:10.1080/15548627.2019.1586257. PMC 6735543. PMID 30806145.
  16. ^ Ikonomov OC, Sbrissa D, Shisheva A (August 2006). "Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion". American Journal of Physiology. Cell Physiology. 291 (2): C393-404. doi:10.1152/ajpcell.00019.2006. PMID 16510848.
  17. ^ a b Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A (August 2007). "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". The Journal of Biological Chemistry. 282 (33): 23878–91. doi:10.1074/jbc.M611678200. PMID 17556371.
  18. ^ Ikonomov OC, Sbrissa D, Shisheva A (July 2001). "Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve". The Journal of Biological Chemistry. 276 (28): 26141–7. doi:10.1074/jbc.M101722200. PMID 11285266.
  19. ^ a b Ikonomov OC, Sbrissa D, Mlak K, Deeb R, Fligger J, Soans A, et al. (December 2003). "Active PIKfyve associates with and promotes the membrane attachment of the late endosome-to-trans-Golgi network transport factor Rab9 effector p40". The Journal of Biological Chemistry. 278 (51): 50863–71. doi:10.1074/jbc.M307260200. PMID 14530284.
  20. ^ Rutherford AC, Traer C, Wassmer T, Pattni K, Bujny MV, Carlton JG, et al. (October 2006). "The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport". Journal of Cell Science. 119 (Pt 19): 3944–57. doi:10.1242/jcs.03153. PMC 1904490. PMID 16954148.
  21. ^ a b Jefferies HB, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, et al. (February 2008). "A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding". EMBO Reports. 9 (2): 164–70. doi:10.1038/sj.embor.7401155. PMC 2246419. PMID 18188180.
  22. ^ Shisheva A (June 2008). "PIKfyve: Partners, significance, debates and paradoxes". Cell Biology International. 32 (6): 591–604. doi:10.1016/j.cellbi.2008.01.006. PMC 2491398. PMID 18304842.
  23. ^ a b Ikonomov OC, Fligger J, Sbrissa D, Dondapati R, Mlak K, Deeb R, Shisheva A (February 2009). "Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin". The Journal of Biological Chemistry. 284 (6): 3750–61. doi:10.1074/jbc.M806539200. PMC 2635046. PMID 19056739.
  24. ^ Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, et al. (July 2005). "Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy". American Journal of Human Genetics. 77 (1): 54–63. doi:10.1086/431346. PMC 1226194. PMID 15902656.
  25. ^ a b Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A (April 2011). "The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice". The Journal of Biological Chemistry. 286 (15): 13404–13. doi:10.1074/jbc.M111.222364. PMC 3075686. PMID 21349843.
  26. ^ Murray JL, Mavrakis M, McDonald NJ, Yilla M, Sheng J, Bellini WJ, et al. (September 2005). "Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus". Journal of Virology. 79 (18): 11742–51. doi:10.1128/JVI.79.18.11742-11751.2005. PMC 1212642. PMID 16140752.
  27. ^ Kerr MC, Wang JT, Castro NA, Hamilton NA, Town L, Brown DL, et al. (April 2010). "Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella". The EMBO Journal. 29 (8): 1331–47. doi:10.1038/emboj.2010.28. PMC 2868569. PMID 20300065.
  28. ^ Ikonomov OC, Sbrissa D, Mlak K, Shisheva A (December 2002). "Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects". Endocrinology. 143 (12): 4742–54. doi:10.1210/en.2002-220615. PMID 12446602.
  29. ^ Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A (July 2007). "ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes". Experimental Cell Research. 313 (11): 2404–16. doi:10.1016/j.yexcr.2007.03.024. PMC 2475679. PMID 17475247.
  30. ^ Ikonomov, O. C.; Sbrissa, D.; Delvecchio, K.; Feng, H. Z.; Cartee, G. D.; Jin, J. P.; Shisheva, A. (2013). "Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching". American Journal of Physiology. Endocrinology and Metabolism. 305 (1): E119-31. doi:10.1152/ajpendo.00030.2013. PMC 3725567. PMID 23673157.
  31. ^ Gayle, S; Landrette, S; Beeharry, N; Conrad, C; Hernandez, M; Beckett, P; Ferguson, SM; Mendelkern, T; Zheng, M; Xu, T; Rothberg, J; Lichenstein, H (2017). "Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma". Blood. 129 (13): 1768–1778. doi:10.1182/blood-2016-09-736892. PMC 5766845. PMID 28104689.
  32. ^ Li, Z; Mbah, NE; Overmeyer, JH; Sarver, JG; George, S; Trabbic, CJ; Erhardt, PW; Maltese, WA (2019). "The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma". BMC Cancer. 19 (1): 77. doi:10.1186/s12885-019-5288-y. PMC 6335761. PMID 30651087.
  33. ^ Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, et al. (February 2019). "A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis". Autophagy. 15 (10): 1694–1718. doi:10.1080/15548627.2019.1586257. PMC 6735543. PMID 30806145.
  34. ^ Sbrissa D, Ikonomov OC, Fenner H, Shisheva A (December 2008). "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality". Journal of Molecular Biology. 384 (4): 766–79. doi:10.1016/j.jmb.2008.10.009. PMC 2756758. PMID 18950639.
  35. ^ Ikonomov OC, Sbrissa D, Fenner H, Shisheva A (December 2009). "PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis". The Journal of Biological Chemistry. 284 (51): 35794–806. doi:10.1074/jbc.M109.037515. PMC 2791009. PMID 19840946.
  36. ^ Tsuruta F, Green EM, Rousset M, Dolmetsch RE (October 2009). "PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death". The Journal of Cell Biology. 187 (2): 279–94. doi:10.1083/jcb.200903028. PMC 2768838. PMID 19841139.
  37. ^ Osborne SL, Wen PJ, Boucheron C, Nguyen HN, Hayakawa M, Kaizawa H, et al. (February 2008). "PIKfyve negatively regulates exocytosis in neurosecretory cells". The Journal of Biological Chemistry. 283 (5): 2804–13. doi:10.1074/jbc.M704856200. PMID 18039667.
  38. ^ Michell RH, Heath VL, Lemmon MA, Dove SK (January 2006). "Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions". Trends in Biochemical Sciences. 31 (1): 52–63. doi:10.1016/j.tibs.2005.11.013. PMID 16364647.
  39. ^ Botelho RJ, Efe JA, Teis D, Emr SD (October 2008). "Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase". Molecular Biology of the Cell. 19 (10): 4273–86. doi:10.1091/mbc.E08-04-0405. PMC 2555960. PMID 18653468.
  40. ^ Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, et al. (December 2008). "VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse". The EMBO Journal. 27 (24): 3221–34. doi:10.1038/emboj.2008.248. PMC 2600653. PMID 19037259.
  41. ^ Yamamoto A, DeWald DB, Boronenkov IV, Anderson RA, Emr SD, Koshland D (May 1995). "Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast". Molecular Biology of the Cell. 6 (5): 525–39. doi:10.1091/mbc.6.5.525. PMC 301213. PMID 7663021.
  42. ^ Rusten TE, Rodahl LM, Pattni K, Englund C, Samakovlis C, Dove S, et al. (September 2006). "Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors". Molecular Biology of the Cell. 17 (9): 3989–4001. doi:10.1091/mbc.E06-03-0239. PMC 1556381. PMID 16837550.
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  44. ^ Whitley P, Hinz S, Doughty J (December 2009). "Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen". Plant Physiology. 151 (4): 1812–22. doi:10.1104/pp.109.146159. PMC 2785992. PMID 19846542.

Further reading edit

  • Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, et al. (February 1999). "Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (1): 63–70. doi:10.1093/dnares/6.1.63. PMID 10231032.
  • Jiao X, Munier FL, Schorderet DF, Zografos L, Smith J, Rubin B, Hejtmancik JF (May 2003). "Genetic linkage of Francois-Neetens fleck (mouchetée) corneal dystrophy to chromosome 2q35". Human Genetics. 112 (5–6): 593–9. doi:10.1007/s00439-002-0905-1. PMID 12607114. S2CID 1338901.
  • Ikonomov OC, Sbrissa D, Foti M, Carpentier JL, Shisheva A (November 2003). "PIKfyve controls fluid phase endocytosis but not recycling/degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis". Molecular Biology of the Cell. 14 (11): 4581–91. doi:10.1091/mbc.E03-04-0222. PMC 266774. PMID 14551253.
  • Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (May 2004). "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Analytical Chemistry. 76 (10): 2763–72. doi:10.1021/ac035352d. PMID 15144186.
  • Sbrissa D, Ikonomov OC, Shisheva A (February 2002). "Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization". The Journal of Biological Chemistry. 277 (8): 6073–9. doi:10.1074/jbc.M110194200. PMID 11706043.
  • Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, et al. (December 2004). "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity". Molecular and Cellular Biology. 24 (23): 10437–47. doi:10.1128/MCB.24.23.10437-10447.2004. PMC 529046. PMID 15542851.
  • Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
  • Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.

December 15, 2023
pikfyve, pikfyve, fyve, finger, containing, phosphoinositide, kinase, enzyme, that, humans, encoded, gene, identifiersaliases, fab1, hel37, pip5k, pip5k3, zfyve29, phosphoinositide, kinase, fyve, type, zinc, finger, containingexternal, idsomim, 609414, 1335106. PIKfyve a FYVE finger containing phosphoinositide kinase is an enzyme that in humans is encoded by the PIKFYVE gene 5 6 PIKFYVEIdentifiersAliasesPIKFYVE CFD FAB1 HEL37 PIP5K PIP5K3 ZFYVE29 phosphoinositide kinase FYVE type zinc finger containingExternal IDsOMIM 609414 MGI 1335106 HomoloGene 32115 GeneCards PIKFYVEGene location Human Chr Chromosome 2 human 1 Band2q34Start208 266 255 bp 1 End208 358 746 bp 1 Gene location Mouse Chr Chromosome 1 mouse 2 Band1 1 C3Start65 225 842 bp 2 End65 317 854 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed insecondary oocyteseminal vesiculacorpus epididymistibiaAchilles tendonjejunal mucosabone marrowsuperficial temporal arteryBrodmann area 46bone marrow cellsTop expressed inciliary bodyretinal pigment epitheliumiriscumulus cellgranular layerpineal glandyolk sacconjunctival fornixtrigeminal ganglionhair follicleMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functiontransferase activity nucleotide binding zinc ion binding 1 phosphatidylinositol 4 phosphate 5 kinase activity metal ion binding kinase activity protein binding phosphatidylinositol phosphate kinase activity ATP binding phosphatidylinositol 3 5 bisphosphate 5 phosphatase activity 1 phosphatidylinositol 3 phosphate 5 kinase activity protein folding chaperone activity unfolded protein bindingCellular componentcytosol endosome early endosome membrane membrane late endosome membrane cell cell junction vesicle membrane Golgi membrane perinuclear region of cytoplasm membrane raft endosome membrane cytoplasmic vesicleBiological processintracellular signal transduction phosphatidylinositol metabolic process phosphorylation myelin assembly receptor mediated endocytosis regulation of autophagosome assembly phosphatidylinositol phosphate biosynthetic process retrograde transport endosome to Golgi phosphatidylinositol 5 phosphate metabolic process protein localization to nucleus phosphatidylinositol biosynthetic process phosphatidylinositol 3 phosphate biosynthetic process de novo protein folding chaperone mediated protein folding protein foldingSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez20057618711EnsemblENSG00000115020ENSMUSG00000025949UniProtQ9Y2I7Q9Z1T6RefSeq mRNA NM 001002881NM 001178000NM 015040NM 152671NM 011086NM 001310624RefSeq protein NP 001171471NP 055855NP 689884NP 001297553NP 035216Location UCSC Chr 2 208 27 208 36 MbChr 1 65 23 65 32 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Medical significance 3 PIKfyve inhibitors as potential therapeutics in Cancer 4 Interactions 5 Evolutionary biology 6 References 7 Further readingFunction editThe principal enzymatic activity of PIKfyve is to phosphorylate PtdIns3P to PtdIns 3 5 P2 PIKfyve activity is responsible for the production of both PtdIns 3 5 P2 and phosphatidylinositol 5 phosphate PtdIns5P 7 8 9 10 PIKfyve is a large protein containing a number of functional domains and expressed in several spliced forms The reported full length mouse and human cDNA clones encode proteins of 2052 and 2098 amino acid residues respectively 6 11 12 13 By directly binding membrane PtdIns 3 P 14 the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes 6 14 Impaired PIKfyve enzymatic activity by dominant interfering mutants siRNA mediated ablation or pharmacological inhibition causes lysosome enlargement and cytoplasmic vacuolation due to impaired PtdIns 3 5 P2 synthesis and impaired lysosome fission process and homeostasis 15 Thus via PtdIns 3 5 P2 production PIKfyve participates in several aspects of vesicular dynamics 16 17 thereby affecting a number of trafficking pathways that emanate from or traverse the endosomal system en route to the trans Golgi network or later compartments along the endocytic pathway 18 19 20 21 22 23 Medical significance editPIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois Neetens corneal fleck dystrophy 24 Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre implantation embryo 25 PIKfyve s role in pathogen invasion is deduced by evidence from cell studies implicating PIKfyve activity in HIV and Salmonella replication 21 26 27 A link of PIKfyve with type 2 diabetes is inferred by the observations that PIKfyve perturbation inhibits insulin regulated glucose uptake 28 29 Concordantly mice with selective Pikfyve gene disruption in skeletal muscle the tissue mainly responsible for the decrease of postprandial blood sugar exhibit systemic insulin resistance glucose intolerance hyperinsulinemia and increased adiposity i e symptoms typical for human prediabetes 30 PIKfyve inhibitors as potential therapeutics in Cancer editSeveral small molecule PIKfyve inhibitors have shown promise as cancer therapeutics in preclinical studies due to selective toxicity in non Hodgkin lymphoma B cells 31 or in U 251 glioblastoma cells 32 PIKfyve inhibitors cause cell death also in A 375 melanoma cells which depend on autophagy for growth and proliferation due to impaired lysosome homeostasis 33 The potential therapeutic use of PIKfyve inhibitors awaits clinical trials Interactions editPIKfyve physically associates with its regulator ArPIKfyve a protein encoded by the human gene VAC14 and the Sac1 domain containing PtdIns 3 5 P2 5 phosphatase Sac3 encoded by FIG4 to form a stable ternary heterooligomeric complex that is scaffolded by ArPIKfyve homooligomeric interactions The presence of two enzymes with opposing activities for PtdIns 3 5 P2 synthesis and turnover in a single complex indicates the requirement for a tight control of PtdIns 3 5 P2 levels 17 34 35 PIKfyve also interacts with the Rab9 effector RABEPK and the kinesin adaptor JLP encoded by SPAG9 19 23 These interactions link PIKfyve to microtubule based endosome to trans Golgi network traffic Under sustained activation of glutamate receptors PIKfyve binds to and facilitates the lysosomal degradation of Cav1 2 voltage dependent calcium channel type 1 2 thereby protecting the neurons from excitotoxicity 36 PIKfyve negatively regulates Ca2 dependent exocytosis in neuroendocrine cells without affecting voltage gated calcium channels 37 Evolutionary biology editPIKFYVE belongs to a large family of evolutionarily conserved lipid kinases Single copy genes encoding similarly structured FYVE domain containing phosphoinositide kinases exist in most genomes from yeast to man The plant A thaliana has several copies of the enzyme Higher eukaryotes after D melanogaster acquire an additional DEP domain The S cerevisiae enzyme Fab1p is required for PtdIns 3 5 P2 synthesis under basal conditions and in response to hyperosmotic shock PtdIns5P made by PIKfyve kinase activity in mammalian cells is not detected in budding yeast 38 Yeast Fab1p associates with Vac14p the ortholog of human ArPIKfyve and Fig4p the ortholog of Sac3 39 The yeast Fab1 complex also includes Vac7p and probably Atg18p proteins that are not detected in the mammalian PIKfyve complex 40 S cerevisiae could survive without Fab1 41 In contrast the knockout of the FYVE domain containing enzymes in A thaliana D melanogaster C elegans and M musculus leads to embryonic lethality indicating that the FYVE domain containing phosphoinositide kinases have become essential in embryonic development of multicellular organisms 25 42 43 44 Thus in evolution the FYVE domain containing phosphoinositide kinases retain several aspects of the structural organization enzyme activity and protein interactions from budding yeast In higher eukaryotes the enzymes acquire one additional domain a role in the production of PtdIns5P a new set of interacting proteins and become essential in embryonic development References edit a b c GRCh38 Ensembl release 89 ENSG00000115020 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000025949 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Entrez Gene Phosphoinositide kinase FYVE finger containing a b c Shisheva A Sbrissa D Ikonomov O January 1999 Cloning characterization and expression of a novel Zn2 binding FYVE finger containing phosphoinositide kinase in insulin sensitive cells Molecular and Cellular Biology 19 1 623 34 doi 10 1128 MCB 19 1 623 PMC 83920 PMID 9858586 Shisheva A 2001 PIKfyve the road to PtdIns 5 P and PtdIns 3 5 P 2 Cell Biology International 25 12 1201 6 doi 10 1006 cbir 2001 0803 PMID 11748912 S2CID 29411107 Sbrissa D Ikonomov OC Deeb R Shisheva A December 2002 Phosphatidylinositol 5 phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells The Journal of Biological Chemistry 277 49 47276 84 doi 10 1074 jbc M207576200 PMID 12270933 Sbrissa D Ikonomov OC Filios C Delvecchio K Shisheva A August 2012 Functional dissociation between PIKfyve synthesized PtdIns5P and PtdIns 3 5 P2 by means of the PIKfyve inhibitor YM201636 American Journal of Physiology Cell Physiology 303 4 C436 46 doi 10 1152 ajpcell 00105 2012 PMC 3422984 PMID 22621786 Zolov SN Bridges D Zhang Y Lee WW Riehle E Verma R et al October 2012 In vivo Pikfyve generates PI 3 5 P2 which serves as both a signaling lipid and the major precursor for PI5P Proceedings of the National Academy of Sciences of the United States of America 109 43 17472 7 Bibcode 2012PNAS 10917472Z doi 10 1073 pnas 1203106109 PMC 3491506 PMID 23047693 Sbrissa D Ikonomov OC Shisheva A July 1999 PIKfyve a mammalian ortholog of yeast Fab1p lipid kinase synthesizes 5 phosphoinositides Effect of insulin The Journal of Biological Chemistry 274 31 21589 97 doi 10 1074 jbc 274 31 21589 PMID 10419465 Sbrissa D Ikonomov OC Deeb R Shisheva A December 2002 Phosphatidylinositol 5 phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells The Journal of Biological Chemistry 277 49 47276 84 doi 10 1074 jbc M207576200 PMID 12270933 Cabezas A Pattni K Stenmark H April 2006 Cloning and subcellular localization of a human phosphatidylinositol 3 phosphate 5 kinase PIKfyve Fab1 Gene 371 1 34 41 doi 10 1016 j gene 2005 11 009 PMID 16448788 a b Sbrissa D Ikonomov OC Shisheva A February 2002 Phosphatidylinositol 3 phosphate interacting domains in PIKfyve Binding specificity and role in PIKfyve Endomenbrane localization The Journal of Biological Chemistry 277 8 6073 9 doi 10 1074 jbc M110194200 PMID 11706043 Sharma G Guardia CM Roy A Vassilev A Saric A Griner LN et al February 2019 A family of PIKFYVE inhibitors with therapeutic potential against autophagy dependent cancer cells disrupt multiple events in lysosome homeostasis Autophagy 15 10 1694 1718 doi 10 1080 15548627 2019 1586257 PMC 6735543 PMID 30806145 Ikonomov OC Sbrissa D Shisheva A August 2006 Localized PtdIns 3 5 P2 synthesis to regulate early endosome dynamics and fusion American Journal of Physiology Cell Physiology 291 2 C393 404 doi 10 1152 ajpcell 00019 2006 PMID 16510848 a b Sbrissa D Ikonomov OC Fu Z Ijuin T Gruenberg J Takenawa T Shisheva A August 2007 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 The Journal of Biological Chemistry 282 33 23878 91 doi 10 1074 jbc M611678200 PMID 17556371 Ikonomov OC Sbrissa D Shisheva A July 2001 Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5 kinase PIKfyve The Journal of Biological Chemistry 276 28 26141 7 doi 10 1074 jbc M101722200 PMID 11285266 a b Ikonomov OC Sbrissa D Mlak K Deeb R Fligger J Soans A et al December 2003 Active PIKfyve associates with and promotes the membrane attachment of the late endosome to trans Golgi network transport factor Rab9 effector p40 The Journal of Biological Chemistry 278 51 50863 71 doi 10 1074 jbc M307260200 PMID 14530284 Rutherford AC Traer C Wassmer T Pattni K Bujny MV Carlton JG et al October 2006 The mammalian phosphatidylinositol 3 phosphate 5 kinase PIKfyve regulates endosome to TGN retrograde transport Journal of Cell Science 119 Pt 19 3944 57 doi 10 1242 jcs 03153 PMC 1904490 PMID 16954148 a b Jefferies HB Cooke FT Jat P Boucheron C Koizumi T Hayakawa M et al February 2008 A selective PIKfyve inhibitor blocks PtdIns 3 5 P 2 production and disrupts endomembrane transport and retroviral budding EMBO Reports 9 2 164 70 doi 10 1038 sj embor 7401155 PMC 2246419 PMID 18188180 Shisheva A June 2008 PIKfyve Partners significance debates and paradoxes Cell Biology International 32 6 591 604 doi 10 1016 j cellbi 2008 01 006 PMC 2491398 PMID 18304842 a b Ikonomov OC Fligger J Sbrissa D Dondapati R Mlak K Deeb R Shisheva A February 2009 Kinesin adapter JLP links PIKfyve to microtubule based endosome to trans Golgi network traffic of furin The Journal of Biological Chemistry 284 6 3750 61 doi 10 1074 jbc M806539200 PMC 2635046 PMID 19056739 Li S Tiab L Jiao X Munier FL Zografos L Frueh BE et al July 2005 Mutations in PIP5K3 are associated with Francois Neetens mouchetee fleck corneal dystrophy American Journal of Human Genetics 77 1 54 63 doi 10 1086 431346 PMC 1226194 PMID 15902656 a b Ikonomov OC Sbrissa D Delvecchio K Xie Y Jin JP Rappolee D Shisheva A April 2011 The phosphoinositide kinase PIKfyve is vital in early embryonic development preimplantation lethality of PIKfyve embryos but normality of PIKfyve mice The Journal of Biological Chemistry 286 15 13404 13 doi 10 1074 jbc M111 222364 PMC 3075686 PMID 21349843 Murray JL Mavrakis M McDonald NJ Yilla M Sheng J Bellini WJ et al September 2005 Rab9 GTPase is required for replication of human immunodeficiency virus type 1 filoviruses and measles virus Journal of Virology 79 18 11742 51 doi 10 1128 JVI 79 18 11742 11751 2005 PMC 1212642 PMID 16140752 Kerr MC Wang JT Castro NA Hamilton NA Town L Brown DL et al April 2010 Inhibition of the PtdIns 5 kinase PIKfyve disrupts intracellular replication of Salmonella The EMBO Journal 29 8 1331 47 doi 10 1038 emboj 2010 28 PMC 2868569 PMID 20300065 Ikonomov OC Sbrissa D Mlak K Shisheva A December 2002 Requirement for PIKfyve enzymatic activity in acute and long term insulin cellular effects Endocrinology 143 12 4742 54 doi 10 1210 en 2002 220615 PMID 12446602 Ikonomov OC Sbrissa D Dondapati R Shisheva A July 2007 ArPIKfyve PIKfyve interaction and role in insulin regulated GLUT4 translocation and glucose transport in 3T3 L1 adipocytes Experimental Cell Research 313 11 2404 16 doi 10 1016 j yexcr 2007 03 024 PMC 2475679 PMID 17475247 Ikonomov O C Sbrissa D Delvecchio K Feng H Z Cartee G D Jin J P Shisheva A 2013 Muscle specific Pikfyve gene disruption causes glucose intolerance insulin resistance adiposity and hyperinsulinemia but not muscle fiber type switching American Journal of Physiology Endocrinology and Metabolism 305 1 E119 31 doi 10 1152 ajpendo 00030 2013 PMC 3725567 PMID 23673157 Gayle S Landrette S Beeharry N Conrad C Hernandez M Beckett P Ferguson SM Mendelkern T Zheng M Xu T Rothberg J Lichenstein H 2017 Identification of apilimod as a first in class PIKfyve kinase inhibitor for treatment of B cell non Hodgkin lymphoma Blood 129 13 1768 1778 doi 10 1182 blood 2016 09 736892 PMC 5766845 PMID 28104689 Li Z Mbah NE Overmeyer JH Sarver JG George S Trabbic CJ Erhardt PW Maltese WA 2019 The JNK signaling pathway plays a key role in methuosis non apoptotic cell death induced by MOMIPP in glioblastoma BMC Cancer 19 1 77 doi 10 1186 s12885 019 5288 y PMC 6335761 PMID 30651087 Sharma G Guardia CM Roy A Vassilev A Saric A Griner LN et al February 2019 A family of PIKFYVE inhibitors with therapeutic potential against autophagy dependent cancer cells disrupt multiple events in lysosome homeostasis Autophagy 15 10 1694 1718 doi 10 1080 15548627 2019 1586257 PMC 6735543 PMID 30806145 Sbrissa D Ikonomov OC Fenner H Shisheva A December 2008 ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality Journal of Molecular Biology 384 4 766 79 doi 10 1016 j jmb 2008 10 009 PMC 2756758 PMID 18950639 Ikonomov OC Sbrissa D Fenner H Shisheva A December 2009 PIKfyve ArPIKfyve Sac3 core complex contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis The Journal of Biological Chemistry 284 51 35794 806 doi 10 1074 jbc M109 037515 PMC 2791009 PMID 19840946 Tsuruta F Green EM Rousset M Dolmetsch RE October 2009 PIKfyve regulates CaV1 2 degradation and prevents excitotoxic cell death The Journal of Cell Biology 187 2 279 94 doi 10 1083 jcb 200903028 PMC 2768838 PMID 19841139 Osborne SL Wen PJ Boucheron C Nguyen HN Hayakawa M Kaizawa H et al February 2008 PIKfyve negatively regulates exocytosis in neurosecretory cells The Journal of Biological Chemistry 283 5 2804 13 doi 10 1074 jbc M704856200 PMID 18039667 Michell RH Heath VL Lemmon MA Dove SK January 2006 Phosphatidylinositol 3 5 bisphosphate metabolism and cellular functions Trends in Biochemical Sciences 31 1 52 63 doi 10 1016 j tibs 2005 11 013 PMID 16364647 Botelho RJ Efe JA Teis D Emr SD October 2008 Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase Molecular Biology of the Cell 19 10 4273 86 doi 10 1091 mbc E08 04 0405 PMC 2555960 PMID 18653468 Jin N Chow CY Liu L Zolov SN Bronson R Davisson M et al December 2008 VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI 3 5 P 2 in yeast and mouse The EMBO Journal 27 24 3221 34 doi 10 1038 emboj 2008 248 PMC 2600653 PMID 19037259 Yamamoto A DeWald DB Boronenkov IV Anderson RA Emr SD Koshland D May 1995 Novel PI 4 P 5 kinase homologue Fab1p essential for normal vacuole function and morphology in yeast Molecular Biology of the Cell 6 5 525 39 doi 10 1091 mbc 6 5 525 PMC 301213 PMID 7663021 Rusten TE Rodahl LM Pattni K Englund C Samakovlis C Dove S et al September 2006 Fab1 phosphatidylinositol 3 phosphate 5 kinase controls trafficking but not silencing of endocytosed receptors Molecular Biology of the Cell 17 9 3989 4001 doi 10 1091 mbc E06 03 0239 PMC 1556381 PMID 16837550 Nicot AS Fares H Payrastre B Chisholm AD Labouesse M Laporte J July 2006 The phosphoinositide kinase PIKfyve Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans Molecular Biology of the Cell 17 7 3062 74 doi 10 1091 mbc E05 12 1120 PMC 1483040 PMID 16801682 Whitley P Hinz S Doughty J December 2009 Arabidopsis FAB1 PIKfyve proteins are essential for development of viable pollen Plant Physiology 151 4 1812 22 doi 10 1104 pp 109 146159 PMC 2785992 PMID 19846542 Further reading editNagase T Ishikawa K Suyama M Kikuno R Hirosawa M Miyajima N et al February 1999 Prediction of the coding sequences of unidentified human genes XIII The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro DNA Research 6 1 63 70 doi 10 1093 dnares 6 1 63 PMID 10231032 Jiao X Munier FL Schorderet DF Zografos L Smith J Rubin B Hejtmancik JF May 2003 Genetic linkage of Francois Neetens fleck mouchetee corneal dystrophy to chromosome 2q35 Human Genetics 112 5 6 593 9 doi 10 1007 s00439 002 0905 1 PMID 12607114 S2CID 1338901 Ikonomov OC Sbrissa D Foti M Carpentier JL Shisheva A November 2003 PIKfyve controls fluid phase endocytosis but not recycling degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis Molecular Biology of the Cell 14 11 4581 91 doi 10 1091 mbc E03 04 0222 PMC 266774 PMID 14551253 Brill LM Salomon AR Ficarro SB Mukherji M Stettler Gill M Peters EC May 2004 Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry Analytical Chemistry 76 10 2763 72 doi 10 1021 ac035352d PMID 15144186 Sbrissa D Ikonomov OC Shisheva A February 2002 Phosphatidylinositol 3 phosphate interacting domains in PIKfyve Binding specificity and role in PIKfyve Endomenbrane localization The Journal of Biological Chemistry 277 8 6073 9 doi 10 1074 jbc M110194200 PMID 11706043 Sbrissa D Ikonomov OC Strakova J Dondapati R Mlak K Deeb R et al December 2004 A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up regulates PIKfyve phosphoinositide 5 kinase activity Molecular and Cellular Biology 24 23 10437 47 doi 10 1128 MCB 24 23 10437 10447 2004 PMC 529046 PMID 15542851 Rush J Moritz A Lee KA Guo A Goss VL Spek EJ et al January 2005 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells Nature Biotechnology 23 1 94 101 doi 10 1038 nbt1046 PMID 15592455 S2CID 7200157 Olsen JV Blagoev B Gnad F Macek B Kumar C Mortensen P Mann M November 2006 Global in vivo and site specific phosphorylation dynamics in signaling networks Cell 127 3 635 48 doi 10 1016 j cell 2006 09 026 PMID 17081983 S2CID 7827573 Retrieved from https en wikipedia org w index php title PIKFYVE amp oldid 1188053361, wikipedia, wiki, book, books, library,

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