PIKFYVE

Phosphoinositide kinase, FYVE finger containing
Identifiers
Symbols PIKFYVE ; CFD; FAB1; HEL37; PIP5K; PIP5K3; ZFYVE29
External IDs OMIM: 609414 MGI: 1335106 HomoloGene: 32115 GeneCards: PIKFYVE Gene
EC number 2.7.1.150
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 200576 18711
Ensembl ENSG00000115020 ENSMUSG00000025949
UniProt Q9Y2I7 Q9Z1T6
RefSeq (mRNA) NM_001002881 NM_011086
RefSeq (protein) NP_001171471 NP_035216
Location (UCSC) Chr 2:
208.27 – 208.36 Mb		 Chr 1:
65.19 – 65.28 Mb
PubMed search

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.[1][2]

Function

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).[3][4][5][6] 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.[2][7][8][9] By directly binding membrane PtdIns(3)P,[10] the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes.[2][10] Impaired PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes endosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis. Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of endosome dynamics,[11][12] 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.[13][14][15][16][17][18]

Medical significance

PIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois-Neetens corneal fleck dystrophy.[19] Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre-implantation embryo.[20] PIKfyve’s role in pathogen invasion is deduced by evidence from cell studies implicating PIKfyve activity in HIV and Salmonella replication.[16][21][22] A link of PIKfyve with type 2 diabetes is inferred by the observations that PIKfyve perturbation inhibits insulin-regulated glucose uptake.[23][24] 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.[25]

Interactions

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.[12][26][27] PIKfyve also interacts with the Rab9 effector RABEPK and the kinesin adaptor JLP, encoded by SPAG9.[14][18] 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.[28] PIKfyve negatively regulates Ca2+-dependent exocytosis in neuroendocrine cells without affecting voltage-gated calcium channels.[29]

Evolutionary biology

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.[30] Yeast Fab1p associates with Vac14p (the ortholog of human ArPIKfyve) and Fig4p (the ortholog of Sac3).[31] The yeast Fab1 complex also includes Vac7p and probably Atg18p, proteins that are not detected in the mammalian PIKfyve complex.[32] S. cerevisiae could survive without Fab1.[33] 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.[20][34][35][36] 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

  1. ↑ "Entrez Gene: Phosphoinositide kinase, FYVE finger containing".
  2. 1 2 3 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". Mol. Cell. Biol. 19 (1): 623–34. PMC 83920. PMID 9858586.
  3. ↑ Shisheva A (2001). "PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2)". Cell Biol. Int. 25 (12): 1201–6. doi:10.1006/cbir.2001.0803. PMID 11748912.
  4. ↑ Sbrissa D, Ikonomov OC, Deeb R, Shisheva A (2002). "Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells". J Biol Chem. 277 (49): 47276–84. doi:10.1074/jbc.M207576200. PMID 12270933.
  5. ↑ Sbrissa D, Ikonomov OC, Filios C, Delvecchio K, Shisheva A (2012). "Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636". Am. J. Physiol., Cell Physiol. 303 (4): C436–46. doi:10.1152/ajpcell.00105.2012. PMC 3422984. PMID 22621786.
  6. ↑ Zolov SN, Bridges D, Zhang Y, Lee WW, Riehle E, Verma R, Lenk GM, Converso-Baran K, Weide T, Albin RL, Saltiel AR, Meisler MH, Russell MW, Weisman LS (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 109 (43): 17472–7. doi:10.1073/pnas.1203106109. PMC 3491506. PMID 23047693.
  7. ↑ Sbrissa D, Ikonomov OC, Shisheva A (July 1999). "PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin". J. Biol. Chem. 274 (31): 21589–97. doi:10.1074/jbc.274.31.21589. PMID 10419465.
  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". J. Biol. Chem. 277 (49): 47276–84. doi:10.1074/jbc.M207576200. PMID 12270933.
  9. ↑ 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.
  10. 1 2 Sbrissa D, Ikonomov OC, Shisheva A (February 2002). "Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization". J. Biol. Chem. 277 (8): 6073–9. doi:10.1074/jbc.M110194200. PMID 11706043.
  11. ↑ Ikonomov OC, Sbrissa D, Shisheva A (August 2006). "Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion". Am. J. Physiol., Cell Physiol. 291 (2): C393–404. doi:10.1152/ajpcell.00019.2006. PMID 16510848.
  12. 1 2 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". J. Biol. Chem. 282 (33): 23878–91. doi:10.1074/jbc.M611678200. PMID 17556371.
  13. ↑ Ikonomov OC, Sbrissa D, Shisheva A (July 2001). "Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve". J. Biol. Chem. 276 (28): 26141–7. doi:10.1074/jbc.M101722200. PMID 11285266.
  14. 1 2 Ikonomov OC, Sbrissa D, Mlak K, Deeb R, Fligger J, Soans A, Finley RL, Shisheva A (December 2003). "Active PIKfyve associates with and promotes the membrane attachment of the late endosome-to-trans-Golgi network transport factor Rab9 effector p40". J. Biol. Chem. 278 (51): 50863–71. doi:10.1074/jbc.M307260200. PMID 14530284.
  15. ↑ Rutherford AC, Traer C, Wassmer T, Pattni K, Bujny MV, Carlton JG, Stenmark H, Cullen PJ (October 2006). "The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport". J. Cell. Sci. 119 (Pt 19): 3944–57. doi:10.1242/jcs.03153. PMC 1904490. PMID 16954148.
  16. 1 2 Jefferies HB, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, Kaizawa H, Ohishi T, Workman P, Waterfield MD, Parker PJ (February 2008). "A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding". EMBO Rep. 9 (2): 164–70. doi:10.1038/sj.embor.7401155. PMC 2246419. PMID 18188180.
  17. ↑ Shisheva A (June 2008). "PIKfyve: Partners, significance, debates and paradoxes". Cell Biol. Int. 32 (6): 591–604. doi:10.1016/j.cellbi.2008.01.006. PMC 2491398. PMID 18304842.
  18. 1 2 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". J. Biol. Chem. 284 (6): 3750–61. doi:10.1074/jbc.M806539200. PMC 2635046. PMID 19056739.
  19. ↑ Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, Sergeev Y, Smith J, Rubin B, Meallet MA, Forster RK, Hejtmancik JF, Schorderet DF (July 2005). "Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy". Am. J. Hum. Genet. 77 (1): 54–63. doi:10.1086/431346. PMC 1226194. PMID 15902656.
  20. 1 2 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". J. Biol. Chem. 286 (15): 13404–13. doi:10.1074/jbc.M111.222364. PMC 3075686. PMID 21349843.
  21. ↑ Murray JL, Mavrakis M, McDonald NJ, Yilla M, Sheng J, Bellini WJ, Zhao L, Le Doux JM, Shaw MW, Luo CC, Lippincott-Schwartz J, Sanchez A, Rubin DH, Hodge TW (September 2005). "Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus". J. Virol. 79 (18): 11742–51. doi:10.1128/JVI.79.18.11742-11751.2005. PMC 1212642. PMID 16140752.
  22. ↑ Kerr MC, Wang JT, Castro NA, Hamilton NA, Town L, Brown DL, Meunier FA, Brown NF, Stow JL, Teasdale RD (April 2010). "Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella". EMBO J. 29 (8): 1331–47. doi:10.1038/emboj.2010.28. PMC 2868569. PMID 20300065.
  23. ↑ 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.
  24. ↑ 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". Exp. Cell Res. 313 (11): 2404–16. doi:10.1016/j.yexcr.2007.03.024. PMC 2475679. PMID 17475247.
  25. ↑ Ikonomov OC, Sbrissa D, Delvecchio K, Feng HZ, Cartee GD, Jin JP, Shisheva A. Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching. Am J Physiol Endocrinol Metab. 2013 Jul 1;305(1):E119-31. doi: 10.1152/ajpendo.00030.2013. Epub 2013 May 14.PMID 23673157
  26. ↑ 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". J. Mol. Biol. 384 (4): 766–79. doi:10.1016/j.jmb.2008.10.009. PMC 2756758. PMID 18950639.
  27. ↑ 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". J. Biol. Chem. 284 (51): 35794–806. doi:10.1074/jbc.M109.037515. PMC 2791009. PMID 19840946.
  28. ↑ Tsuruta F, Green EM, Rousset M, Dolmetsch RE (October 2009). "PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death". J. Cell Biol. 187 (2): 279–94. doi:10.1083/jcb.200903028. PMC 2768838. PMID 19841139.
  29. ↑ Osborne SL, Wen PJ, Boucheron C, Nguyen HN, Hayakawa M, Kaizawa H, Parker PJ, Vitale N, Meunier FA (February 2008). "PIKfyve negatively regulates exocytosis in neurosecretory cells". J. Biol. Chem. 283 (5): 2804–13. doi:10.1074/jbc.M704856200. PMID 18039667.
  30. ↑ Michell RH, Heath VL, Lemmon MA, Dove SK (January 2006). "Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions". Trends Biochem. Sci. 31 (1): 52–63. doi:10.1016/j.tibs.2005.11.013. PMID 16364647.
  31. ↑ Botelho RJ, Efe JA, Teis D, Emr SD (October 2008). "Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase". Mol. Biol. Cell 19 (10): 4273–86. doi:10.1091/mbc.E08-04-0405. PMC 2555960. PMID 18653468.
  32. ↑ Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS (December 2008). "VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse". EMBO J. 27 (24): 3221–34. doi:10.1038/emboj.2008.248. PMC 2600653. PMID 19037259.
  33. ↑ 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". Mol. Biol. Cell 6 (5): 525–39. doi:10.1091/mbc.6.5.525. PMC 301213. PMID 7663021.
  34. ↑ Rusten TE, Rodahl LM, Pattni K, Englund C, Samakovlis C, Dove S, Brech A, Stenmark H (September 2006). "Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors". Mol. Biol. Cell 17 (9): 3989–4001. doi:10.1091/mbc.E06-03-0239. PMC 1556381. PMID 16837550.
  35. ↑ 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". Mol. Biol. Cell 17 (7): 3062–74. doi:10.1091/mbc.E05-12-1120. PMC 1483040. PMID 16801682.
  36. ↑ Whitley P, Hinz S, Doughty J (December 2009). "Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen". Plant Physiol. 151 (4): 1812–22. doi:10.1104/pp.109.146159. PMC 2785992. PMID 19846542.

Further reading

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