Biology:PIKFYVE

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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 lysosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis and impaired lysosome fission process and homeostasis.[11] Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of vesicular dynamics,[12][13] 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.[14][15][16][17][18][19]

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.[20] Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre-implantation embryo.[21] PIKfyve’s role in pathogen invasion is deduced by evidence from cell studies implicating PIKfyve activity in HIV and Salmonella replication.[17][22][23] A link of PIKfyve with type 2 diabetes is inferred by the observations that PIKfyve perturbation inhibits insulin-regulated glucose uptake.[24][25] 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.[26]

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 [27] or in U-251 glioblastoma cells. [28] PIKfyve inhibitors cause cell death also in A-375 melanoma cells, which depend on autophagy for growth and proliferation, due to impaired lysosome homeostasis. [29] 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.[13][30][31] PIKfyve also interacts with the Rab9 effector RABEPK and the kinesin adaptor JLP, encoded by SPAG9.[15][19] 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.[32] PIKfyve negatively regulates Ca2+-dependent exocytosis in neuroendocrine cells without affecting voltage-gated calcium channels.[33]

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.[34] Yeast Fab1p associates with Vac14p (the ortholog of human ArPIKfyve) and Fig4p (the ortholog of Sac3).[35] The yeast Fab1 complex also includes Vac7p and probably Atg18p, proteins that are not detected in the mammalian PIKfyve complex.[36] S. cerevisiae could survive without Fab1.[37] 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.[21][38][39][40] 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". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=200576. 
  2. ↑ 2.0 2.1 2.2 "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. January 1999. doi:10.1128/MCB.19.1.623. PMID 9858586. 
  3. ↑ "PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2)". Cell Biology International 25 (12): 1201–6. 2001. doi:10.1006/cbir.2001.0803. PMID 11748912. 
  4. ↑ "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. December 2002. doi:10.1074/jbc.M207576200. PMID 12270933. 
  5. ↑ "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. August 2012. doi:10.1152/ajpcell.00105.2012. PMID 22621786. 
  6. ↑ "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. October 2012. doi:10.1073/pnas.1203106109. PMID 23047693. Bibcode: 2012PNAS..10917472Z. 
  7. ↑ "PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin". The Journal of Biological Chemistry 274 (31): 21589–97. July 1999. doi:10.1074/jbc.274.31.21589. PMID 10419465. 
  8. ↑ "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. December 2002. doi:10.1074/jbc.M207576200. PMID 12270933. 
  9. ↑ "Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1". Gene 371 (1): 34–41. April 2006. doi:10.1016/j.gene.2005.11.009. PMID 16448788. 
  10. ↑ 10.0 10.1 "Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization". The Journal of Biological Chemistry 277 (8): 6073–9. February 2002. doi:10.1074/jbc.M110194200. PMID 11706043. 
  11. ↑ "A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis". Autophagy 15 (10): 1694–1718. February 2019. doi:10.1080/15548627.2019.1586257. PMID 30806145. 
  12. ↑ "Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion". American Journal of Physiology. Cell Physiology 291 (2): C393-404. August 2006. doi:10.1152/ajpcell.00019.2006. PMID 16510848. 
  13. ↑ 13.0 13.1 "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. August 2007. doi:10.1074/jbc.M611678200. PMID 17556371. 
  14. ↑ "Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve". The Journal of Biological Chemistry 276 (28): 26141–7. July 2001. doi:10.1074/jbc.M101722200. PMID 11285266. 
  15. ↑ 15.0 15.1 "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. December 2003. doi:10.1074/jbc.M307260200. PMID 14530284. 
  16. ↑ "The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport". Journal of Cell Science 119 (Pt 19): 3944–57. October 2006. doi:10.1242/jcs.03153. PMID 16954148. 
  17. ↑ 17.0 17.1 "A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding". EMBO Reports 9 (2): 164–70. February 2008. doi:10.1038/sj.embor.7401155. PMID 18188180. 
  18. ↑ "PIKfyve: Partners, significance, debates and paradoxes". Cell Biology International 32 (6): 591–604. June 2008. doi:10.1016/j.cellbi.2008.01.006. PMID 18304842. 
  19. ↑ 19.0 19.1 "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. February 2009. doi:10.1074/jbc.M806539200. PMID 19056739. 
  20. ↑ "Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy". American Journal of Human Genetics 77 (1): 54–63. July 2005. doi:10.1086/431346. PMID 15902656. 
  21. ↑ 21.0 21.1 "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. April 2011. doi:10.1074/jbc.M111.222364. PMID 21349843. 
  22. ↑ "Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus". Journal of Virology 79 (18): 11742–51. September 2005. doi:10.1128/JVI.79.18.11742-11751.2005. PMID 16140752. 
  23. ↑ "Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella". The EMBO Journal 29 (8): 1331–47. April 2010. doi:10.1038/emboj.2010.28. PMID 20300065. 
  24. ↑ "Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects". Endocrinology 143 (12): 4742–54. December 2002. doi:10.1210/en.2002-220615. PMID 12446602. 
  25. ↑ "ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes". Experimental Cell Research 313 (11): 2404–16. July 2007. doi:10.1016/j.yexcr.2007.03.024. PMID 17475247. 
  26. ↑ 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. PMID 23673157. 
  27. ↑ Gayle, S; Landrette, S; Beeharry, N; Conrad, C; Hernandez, M; Beckett, P; Ferguson, SM; Mendelkern, T et al. (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. PMID 28104689. 
  28. ↑ 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. PMID 30651087. 
  29. ↑ "A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis". Autophagy 15 (10): 1694–1718. February 2019. doi:10.1080/15548627.2019.1586257. PMID 30806145. 
  30. ↑ "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. December 2008. doi:10.1016/j.jmb.2008.10.009. PMID 18950639. 
  31. ↑ "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. December 2009. doi:10.1074/jbc.M109.037515. PMID 19840946. 
  32. ↑ "PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death". The Journal of Cell Biology 187 (2): 279–94. October 2009. doi:10.1083/jcb.200903028. PMID 19841139. 
  33. ↑ "PIKfyve negatively regulates exocytosis in neurosecretory cells". The Journal of Biological Chemistry 283 (5): 2804–13. February 2008. doi:10.1074/jbc.M704856200. PMID 18039667. 
  34. ↑ "Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions". Trends in Biochemical Sciences 31 (1): 52–63. January 2006. doi:10.1016/j.tibs.2005.11.013. PMID 16364647. 
  35. ↑ "Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase". Molecular Biology of the Cell 19 (10): 4273–86. October 2008. doi:10.1091/mbc.E08-04-0405. PMID 18653468. 
  36. ↑ "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. December 2008. doi:10.1038/emboj.2008.248. PMID 19037259. 
  37. ↑ "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. May 1995. doi:10.1091/mbc.6.5.525. PMID 7663021. 
  38. ↑ "Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors". Molecular Biology of the Cell 17 (9): 3989–4001. September 2006. doi:10.1091/mbc.E06-03-0239. PMID 16837550. 
  39. ↑ "The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans". Molecular Biology of the Cell 17 (7): 3062–74. July 2006. doi:10.1091/mbc.E05-12-1120. PMID 16801682. 
  40. ↑ "Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen". Plant Physiology 151 (4): 1812–22. December 2009. doi:10.1104/pp.109.146159. PMID 19846542. 

Further reading




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