View source for PIKFYVE

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''PIKfyve''', a [[FYVE finger]]-containing phosphoinositide kinase, is an [[enzyme]] that in humans is encoded by the ''PIKFYVE'' [[gene]].<ref name="entrez"/><ref name ="Shisheva_1999"/>
== Function ==
The principal enzymatic activity of PIKfyve is to phosphorylate [[phosphatidylinositol 3-phosphate|PtdIns3P]] to [[phosphatidylinositol 3,5-bisphosphate|PtdIns(3,5)P2]]. PIKfyve activity is responsible for the production of both PtdIns(3,5)P2 and [[phosphatidylinositol 5-phosphate]] (PtdIns5P).<ref name="Shisheva_2001">{{cite journal | vauthors = Shisheva A | title = PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2) | journal = Cell Biology International | volume = 25 | issue = 12 | pages = 1201–6 | year = 2001 | pmid = 11748912 | doi = 10.1006/cbir.2001.0803 | s2cid = 29411107 }}</ref><ref name="Sbrissa_2002b"/><ref name="pmid 22621786">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Filios C, Delvecchio K, Shisheva A | title = Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636 | journal = American Journal of Physiology. Cell Physiology | volume = 303 | issue = 4 | pages = C436-46 | date = August 2012 | pmid = 22621786 | pmc = 3422984 | doi = 10.1152/ajpcell.00105.2012 }}</ref><ref name="Zolov_2012">{{cite journal | vauthors = 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 | display-authors = 6 | title = In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 43 | pages = 17472–7 | date = October 2012 | pmid = 23047693 | pmc = 3491506 | doi = 10.1073/pnas.1203106109 | bibcode = 2012PNAS..10917472Z | doi-access = free }}</ref> 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.<ref name="Shisheva_1999"/><ref name="Sbrissa_1999"/><ref name="Sbrissa_2002b"/><ref name="Cabezas_2006"/> By directly binding membrane PtdIns(3)P,<ref name="Sbrissa_2002a"/> the [[FYVE domain|FYVE finger domain]] of PIKfyve is essential in localizing the protein to the cytosolic leaflet of [[endosome]]s.<ref name ="Shisheva_1999"/><ref name="Sbrissa_2002a"/> Impaired  PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes lysosome enlargement and cytoplasmic [[vacuole|vacuolation]] due to impaired PtdIns(3,5)P2 synthesis and impaired lysosome fission process and homeostasis.<ref>{{cite journal | vauthors = Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, Marugan J, Ferrer M, Bonifacino JS, DePamphilis ML | display-authors = 6 | title = A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis | journal = Autophagy | volume = 15 | issue = 10 | pages = 1694–1718 | date = February 2019 | pmid = 30806145 | pmc = 6735543 | doi = 10.1080/15548627.2019.1586257 }}</ref> Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of vesicular dynamics,<ref name="Ikonomov_2006"/><ref name="Sbrissa_2007"/> 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.<ref name="Ikonomov_2001"/><ref name="Ikonomov_2003"/><ref name="Rutherford_2006"/><ref name="Jefferies_2008"/><ref name="Shisheva_2008"/><ref name="Ikonomov_2009a"/>
== Medical significance ==
PIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois-Neetens [[fleck corneal dystrophy|corneal fleck dystrophy]].<ref name="Li_2005"/> Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre-implantation embryo.<ref name="Ikonomov_2011"/> PIKfyve’s role in pathogen invasion is deduced by evidence from cell studies implicating PIKfyve activity in [[HIV]] and [[Salmonella]] replication.<ref name="Jefferies_2008"/><ref name="Murray_2005"/><ref name="Kerr_2010"/> A link of PIKfyve with type 2 diabetes is inferred by the observations that PIKfyve perturbation inhibits insulin-regulated glucose uptake.<ref name="Ikonomov_2002"/><ref name="Ikonomov_2007"/> 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]].<ref>{{cite journal |pmid=23673157|pmc=3725567|year=2013|last1=Ikonomov|first1=O. C.|title=Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching|journal=American Journal of Physiology. Endocrinology and Metabolism|volume=305|issue=1|pages=E119-31|last2=Sbrissa|first2=D.|last3=Delvecchio|first3=K.|last4=Feng|first4=H. Z.|last5=Cartee|first5=G. D.|last6=Jin|first6=J. P.|last7=Shisheva|first7=A.|doi=10.1152/ajpendo.00030.2013}}</ref>
== PIKfyve inhibitors as potential therapeutics in Cancer ==
Several small molecule PIKfyve inhibitors have shown promise  as cancer therapeutics in preclinical studies due to selective toxicity in non-Hodgkin lymphoma B cells <ref>{{Cite journal|last1=Gayle|first1=S|last2=Landrette|first2=S|last3=Beeharry|first3=N|last4=Conrad|first4=C|last5=Hernandez|first5=M|last6=Beckett|first6=P|last7=Ferguson|first7=SM|last8=Mendelkern|first8=T|last9=Zheng|first9=M|last10=Xu|first10=T|last11=Rothberg|first11=J|last12=Lichenstein|first12=H|title=Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma|journal=Blood |volume=129|issue=13|pages=1768–1778|doi=10.1182/blood-2016-09-736892|pmid=28104689|pmc=5766845|year=2017}}</ref> or in U-251 [[glioblastoma]] cells. <ref>{{Cite journal|last1=Li|first1=Z|last2=Mbah|first2=NE|last3=Overmeyer|first3=JH|last4=Sarver|first4=JG|last5=George|first5=S|last6=Trabbic|first6=CJ|last7=Erhardt|first7=PW|last8=Maltese|first8=WA|title=The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma|journal=BMC Cancer |volume=19|issue=1|pages=77|doi=10.1186/s12885-019-5288-y|pmid=30651087|pmc=6335761|year=2019|doi-access=free}}</ref>
PIKfyve inhibitors cause cell death also in A-375 melanoma cells, which depend on autophagy for growth and proliferation, due to impaired lysosome homeostasis. <ref>{{cite journal | vauthors = Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, Marugan J, Ferrer M, Bonifacino JS, DePamphilis ML | display-authors = 6 | title = A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis | journal = Autophagy | volume = 15 | issue = 10 | pages = 1694–1718 | date = February 2019 | pmid = 30806145 | pmc = 6735543 | doi = 10.1080/15548627.2019.1586257 }}</ref>  The potential therapeutic use of PIKfyve inhibitors awaits clinical trials.
== 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.<ref name="Sbrissa_2007"/><ref name="Sbrissa_2008"/><ref name="Ikonomov_2009b"/> PIKfyve also interacts with the [[RAB9A|Rab9]] effector [[RABEPK]] and the kinesin adaptor JLP, encoded by [[SPAG9]].<ref name="Ikonomov_2003"/><ref name="Ikonomov_2009a"/> These interactions link PIKfyve to [[microtubule]]-based endosome to [[Golgi apparatus|trans-Golgi network]] traffic. Under sustained activation of [[glutamate receptor]]s PIKfyve binds to and facilitates the [[lysosome|lysosomal]] degradation of [[Cav1.2|Ca<sub>v</sub>1.2]], voltage-dependent calcium channel type 1.2, thereby protecting the neurons from excitotoxicity.<ref name="Tsuruta_2009"/> PIKfyve negatively regulates Ca<sup>2+</sup>-dependent [[exocytosis]] in [[neuroendocrine cell]]s  without affecting voltage-gated calcium channels.<ref name="Osborne_2008"/>
== 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 ''[[Arabidopsis thaliana|A. thaliana]]'' has several copies of the enzyme. Higher eukaryotes (after ''[[Drosophila melanogaster|D. melanogaster]]''), acquire an additional [[DEP domain]]. The ''[[Saccharomyces cerevisiae|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.<ref name="Michell_2006"/> Yeast Fab1p associates with Vac14p (the ortholog of human ArPIKfyve) and Fig4p (the ortholog of Sac3).<ref name="Botelho_2008"/> The yeast Fab1 complex also includes Vac7p and probably Atg18p, proteins that are not detected in the mammalian PIKfyve complex.<ref name="Jin_2008"/> ''S. cerevisiae'' could survive without Fab1.<ref name="Yamamoto_1995"/> In contrast, the knockout of the FYVE domain-containing enzymes in ''A. thaliana'', ''D. melanogaster'', ''[[Caenorhabditis elegans|C. elegans]]'' and ''[[Mus musculus|M. musculus]]''  leads to embryonic lethality indicating that the FYVE-domain–containing phosphoinositide kinases have become essential in embryonic development of multicellular organisms.<ref name="Ikonomov_2011"/><ref name="Rusten_2006"/><ref name="Nicot_2006"/><ref name="Whitley_2009"/> 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 ==
{{Reflist|2|refs=
<ref name="entrez">{{Cite web| title = Entrez Gene: Phosphoinositide kinase, FYVE finger containing | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=200576| access-date = }}</ref>
<ref name="Botelho_2008">{{cite journal | vauthors = Botelho RJ, Efe JA, Teis D, Emr SD | title = Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase | journal = Molecular Biology of the Cell | volume = 19 | issue = 10 | pages = 4273–86 | date = October 2008 | pmid = 18653468 | pmc = 2555960 | doi = 10.1091/mbc.E08-04-0405 }}</ref>
<ref name="Cabezas_2006">{{cite journal | vauthors = Cabezas A, Pattni K, Stenmark H | title = Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1 | journal = Gene | volume = 371 | issue = 1 | pages = 34–41 | date = April 2006 | pmid = 16448788 | doi = 10.1016/j.gene.2005.11.009 }}</ref>
<ref name="Ikonomov_2001">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Shisheva A | title = Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve | journal = The Journal of Biological Chemistry | volume = 276 | issue = 28 | pages = 26141–7 | date = July 2001 | pmid = 11285266 | doi = 10.1074/jbc.M101722200 | doi-access = free }}</ref>
<ref name="Ikonomov_2002">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Mlak K, Shisheva A | title = Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects | journal = Endocrinology | volume = 143 | issue = 12 | pages = 4742–54 | date = December 2002 | pmid = 12446602 | doi = 10.1210/en.2002-220615 | doi-access = free }}</ref>
<ref name="Ikonomov_2003">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Mlak K, Deeb R, Fligger J, Soans A, Finley RL, Shisheva A | display-authors = 6 | title = Active PIKfyve associates with and promotes the membrane attachment of the late endosome-to-trans-Golgi network transport factor Rab9 effector p40 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 51 | pages = 50863–71 | date = December 2003 | pmid = 14530284 | doi = 10.1074/jbc.M307260200 | doi-access = free }}</ref>
<ref name="Ikonomov_2006">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Shisheva A | title = Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion | journal = American Journal of Physiology. Cell Physiology | volume = 291 | issue = 2 | pages = C393-404 | date = August 2006 | pmid = 16510848 | doi = 10.1152/ajpcell.00019.2006 | citeseerx = 10.1.1.318.2620 }}</ref>
<ref name="Ikonomov_2007">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A | title = ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes | journal = Experimental Cell Research | volume = 313 | issue = 11 | pages = 2404–16 | date = July 2007 | pmid = 17475247 | pmc = 2475679 | doi = 10.1016/j.yexcr.2007.03.024 }}</ref>
<ref name="Ikonomov_2009a">{{cite journal | vauthors = Ikonomov OC, Fligger J, Sbrissa D, Dondapati R, Mlak K, Deeb R, Shisheva A | title = Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin | journal = The Journal of Biological Chemistry | volume = 284 | issue = 6 | pages = 3750–61 | date = February 2009 | pmid = 19056739 | pmc = 2635046 | doi = 10.1074/jbc.M806539200 | doi-access = free }}</ref>
<ref name="Ikonomov_2009b">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Fenner H, Shisheva A | title = PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis | journal = The Journal of Biological Chemistry | volume = 284 | issue = 51 | pages = 35794–806 | date = December 2009 | pmid = 19840946 | pmc = 2791009 | doi = 10.1074/jbc.M109.037515 | doi-access = free }}</ref>
<ref name="Ikonomov_2011">{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A | title = The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice | journal = The Journal of Biological Chemistry | volume = 286 | issue = 15 | pages = 13404–13 | date = April 2011 | pmid = 21349843 | pmc = 3075686 | doi = 10.1074/jbc.M111.222364 | doi-access = free }}</ref>
<ref name="Jefferies_2008">{{cite journal | vauthors = Jefferies HB, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, Kaizawa H, Ohishi T, Workman P, Waterfield MD, Parker PJ | display-authors = 6 | title = A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding | journal = EMBO Reports | volume = 9 | issue = 2 | pages = 164–70 | date = February 2008 | pmid = 18188180 | pmc = 2246419 | doi = 10.1038/sj.embor.7401155 }}</ref>
<ref name="Jin_2008">{{cite journal | vauthors = 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 | display-authors = 6 | title = VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse | journal = The EMBO Journal | volume = 27 | issue = 24 | pages = 3221–34 | date = December 2008 | pmid = 19037259 | pmc = 2600653 | doi = 10.1038/emboj.2008.248 }}</ref>
<ref name="Kerr_2010">{{cite journal | vauthors = Kerr MC, Wang JT, Castro NA, Hamilton NA, Town L, Brown DL, Meunier FA, Brown NF, Stow JL, Teasdale RD | display-authors = 6 | title = Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella | journal = The EMBO Journal | volume = 29 | issue = 8 | pages = 1331–47 | date = April 2010 | pmid = 20300065 | pmc = 2868569 | doi = 10.1038/emboj.2010.28 }}</ref>
<ref name="Li_2005">{{cite journal | vauthors = 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 | display-authors = 6 | title = Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy | journal = American Journal of Human Genetics | volume = 77 | issue = 1 | pages = 54–63 | date = July 2005 | pmid = 15902656 | pmc = 1226194 | doi = 10.1086/431346 }}</ref>
<ref name="Michell_2006">{{cite journal | vauthors = Michell RH, Heath VL, Lemmon MA, Dove SK | title = Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions | journal = Trends in Biochemical Sciences | volume = 31 | issue = 1 | pages = 52–63 | date = January 2006 | pmid = 16364647 | doi = 10.1016/j.tibs.2005.11.013 }}</ref>
<ref name="Murray_2005">{{cite journal | vauthors = 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 | display-authors = 6 | title = Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus | journal = Journal of Virology | volume = 79 | issue = 18 | pages = 11742–51 | date = September 2005 | pmid = 16140752 | pmc = 1212642 | doi = 10.1128/JVI.79.18.11742-11751.2005 }}</ref>
<ref name="Nicot_2006">{{cite journal | vauthors = Nicot AS, Fares H, Payrastre B, Chisholm AD, Labouesse M, Laporte J | title = The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans | journal = Molecular Biology of the Cell | volume = 17 | issue = 7 | pages = 3062–74 | date = July 2006 | pmid = 16801682 | pmc = 1483040 | doi = 10.1091/mbc.E05-12-1120 }}</ref>
<ref name="Osborne_2008">{{cite journal | vauthors = Osborne SL, Wen PJ, Boucheron C, Nguyen HN, Hayakawa M, Kaizawa H, Parker PJ, Vitale N, Meunier FA | display-authors = 6 | title = PIKfyve negatively regulates exocytosis in neurosecretory cells | journal = The Journal of Biological Chemistry | volume = 283 | issue = 5 | pages = 2804–13 | date = February 2008 | pmid = 18039667 | doi = 10.1074/jbc.M704856200 | doi-access = free }}</ref>
<ref name="Rusten_2006">{{cite journal | vauthors = Rusten TE, Rodahl LM, Pattni K, Englund C, Samakovlis C, Dove S, Brech A, Stenmark H | display-authors = 6 | title = Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors | journal = Molecular Biology of the Cell | volume = 17 | issue = 9 | pages = 3989–4001 | date = September 2006 | pmid = 16837550 | pmc = 1556381 | doi = 10.1091/mbc.E06-03-0239 }}</ref>
<ref name="Rutherford_2006">{{cite journal | vauthors = Rutherford AC, Traer C, Wassmer T, Pattni K, Bujny MV, Carlton JG, Stenmark H, Cullen PJ | display-authors = 6 | title = The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport | journal = Journal of Cell Science | volume = 119 | issue = Pt 19 | pages = 3944–57 | date = October 2006 | pmid = 16954148 | pmc = 1904490 | doi = 10.1242/jcs.03153 }}</ref>
<ref name="Sbrissa_1999">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Shisheva A | title = PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin | journal = The Journal of Biological Chemistry | volume = 274 | issue = 31 | pages = 21589–97 | date = July 1999 | pmid = 10419465 | doi = 10.1074/jbc.274.31.21589 | doi-access = free }}</ref>
<ref name="Sbrissa_2002a">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Shisheva A | title = Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 6073–9 | date = February 2002 | pmid = 11706043 | doi = 10.1074/jbc.M110194200 | doi-access = free }}</ref>
<ref name="Sbrissa_2002b">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Deeb R, Shisheva A | title = Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 49 | pages = 47276–84 | date = December 2002 | pmid = 12270933 | doi = 10.1074/jbc.M207576200 | doi-access = free }}</ref>
<ref name="Sbrissa_2007">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A | title = 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 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 33 | pages = 23878–91 | date = August 2007 | pmid = 17556371 | doi = 10.1074/jbc.M611678200 | doi-access = free }}</ref>
<ref name="Sbrissa_2008">{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Fenner H, Shisheva A | title = ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality | journal = Journal of Molecular Biology | volume = 384 | issue = 4 | pages = 766–79 | date = December 2008 | pmid = 18950639 | pmc = 2756758 | doi = 10.1016/j.jmb.2008.10.009 }}</ref>
<ref name="Shisheva_1999">{{cite journal | vauthors = Shisheva A, Sbrissa D, Ikonomov O | title = Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 623–34 | date = January 1999 | pmid = 9858586 | pmc = 83920 | doi = 10.1128/MCB.19.1.623 }}</ref>
<ref name="Shisheva_2008">{{cite journal | vauthors = Shisheva A | title = PIKfyve: Partners, significance, debates and paradoxes | journal = Cell Biology International | volume = 32 | issue = 6 | pages = 591–604 | date = June 2008 | pmid = 18304842 | pmc = 2491398 | doi = 10.1016/j.cellbi.2008.01.006 }}</ref>
<ref name="Tsuruta_2009">{{cite journal | vauthors = Tsuruta F, Green EM, Rousset M, Dolmetsch RE | title = PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death | journal = The Journal of Cell Biology | volume = 187 | issue = 2 | pages = 279–94 | date = October 2009 | pmid = 19841139 | pmc = 2768838 | doi = 10.1083/jcb.200903028 }}</ref>
<ref name="Whitley_2009">{{cite journal | vauthors = Whitley P, Hinz S, Doughty J | title = Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen | journal = Plant Physiology | volume = 151 | issue = 4 | pages = 1812–22 | date = December 2009 | pmid = 19846542 | pmc = 2785992 | doi = 10.1104/pp.109.146159 }}</ref>
<ref name="Yamamoto_1995">{{cite journal | vauthors = Yamamoto A, DeWald DB, Boronenkov IV, Anderson RA, Emr SD, Koshland D | title = Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast | journal = Molecular Biology of the Cell | volume = 6 | issue = 5 | pages = 525–39 | date = May 1995 | pmid = 7663021 | pmc = 301213 | doi = 10.1091/mbc.6.5.525 }}</ref>
}}
== Further reading ==
{{Refbegin|35em}}
* {{cite journal | vauthors = Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | display-authors = 6 | title = 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 | journal = DNA Research | volume = 6 | issue = 1 | pages = 63–70 | date = February 1999 | pmid = 10231032 | doi = 10.1093/dnares/6.1.63 | doi-access = free }}
* {{cite journal | vauthors = Jiao X, Munier FL, Schorderet DF, Zografos L, Smith J, Rubin B, Hejtmancik JF | title = Genetic linkage of Francois-Neetens fleck (mouchetée) corneal dystrophy to chromosome 2q35 | journal = Human Genetics | volume = 112 | issue = 5–6 | pages = 593–9 | date = May 2003 | pmid = 12607114 | doi = 10.1007/s00439-002-0905-1 | s2cid = 1338901 }}
* {{cite journal | vauthors = Ikonomov OC, Sbrissa D, Foti M, Carpentier JL, Shisheva A | title = PIKfyve controls fluid phase endocytosis but not recycling/degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis | journal = Molecular Biology of the Cell | volume = 14 | issue = 11 | pages = 4581–91 | date = November 2003 | pmid = 14551253 | pmc = 266774 | doi = 10.1091/mbc.E03-04-0222 }}
* {{cite journal | vauthors = Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC | title = Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry | journal = Analytical Chemistry | volume = 76 | issue = 10 | pages = 2763–72 | date = May 2004 | pmid = 15144186 | doi = 10.1021/ac035352d }}
* {{cite journal | vauthors = Sbrissa D, Ikonomov OC, Shisheva A | title = Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 6073–9 | date = February 2002 | pmid = 11706043 | doi = 10.1074/jbc.M110194200 | doi-access = free }}
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