PIKFYVE

PIKFYVE
Identifikatori
Aliasi	PIKFYVE
Vanjski ID-jevi	OMIM: 609414 MGI: 1335106 HomoloGene: 32115 GeneCards: PIKFYVE
Lokacija gena (čovjek) Hrom. Hromosom 2 (čovjek)[1] Bend 2q34 Početak 208,266,255 bp[1] Kraj 208,358,746 bp[1]
Lokacija gena (miš) Hrom. Hromosom 1 (miš)[2] Bend 1|1 C3 Početak 65,225,842 bp[2] Kraj 65,317,854 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • aktivnost sa transferazom • nucleotide binding • vezivanje iona cinka • 1-phosphatidylinositol-4-phosphate 5-kinase activity • vezivanje iona metala • kinase activity • GO:0001948, GO:0016582 vezivanje za proteine • 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 binding Ćelijska komponenta • citosol • endozom • early endosome membrane • membrana • late endosome membrane • cell-cell junction • vesicle membrane • Golđijeva membrana • perinuklearno područje citoplazme • Lipidni splav • endosome membrane • GO:0016023 citoplazmatska vezikula Biološki proces • GO:0007243 intracellular signal transduction • phosphatidylinositol metabolic process • Fosforilacija • 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 • Savijanje proteina Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	200576	18711
Ensembl	ENSG00000115020	ENSMUSG00000025949
UniProt	Q9Y2I7	Q9Z1T6
RefSeq (mRNK)	NM_001002881 NM_001178000 NM_015040 NM_152671	NM_011086 NM_001310624
RefSeq (bjelančevina)	NP_001171471 NP_055855 NP_689884	NP_001297553 NP_035216
Lokacija (UCSC)	Chr 2: 208.27 – 208.36 Mb	Chr 1: 65.23 – 65.32 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

FYVE prst s fosfoinozitid-kinazom (PIKfyve) je enzim koji je kod ljudi kodiran genom PIKFYVE.^[5]

Funkcija

Glavna enzimska aktivnost PIKfyve je fosforilacija PtdIns3P-a u PtdIns (3,5) P2. Aktivnost PIKfyve-a odgovorna je za proizvodnju i PtdIns (3,5) P2 i fosfatidilinozitol 5-fosfata (PtdIns5P).^[6][7][8][9] PIKfyve je veliki protein koji sadrži brojne funkcijske domene i izražen je u nekoliko spojenih oblika. Prijavljeni klonovi miša pune dužine i ljudske cDNK, kodiraju proteine 2052, odnosno 2098 aminokiselinskih ostataka.^{[7][10][11][12]} Direktnim vezanjem membrane PtdIns(3)P,^[13] Domen FYVE prsta PIKfyve je presudan za lokalizaciju proteina u citosolnom listiću endosoma.^[10][13] Rasparena enzimska aktivnost PIKfyve dominantno ometajućim mutantima, ablacija posredovana putem siRNK ili farmakološka inhibicija uzrokuju povećanje lizosoma i citoplazmatsku vakuolaciju zbog poremećene sinteze PtdIns (3,5) P2 i oštećenog procesa fisije lizosoma i homeostaze.^[14] Dakle, putem proizvodnje PtdIns (3,5) P2, PIKfyve učestvuje u nekoliko aspekata vezikulske dinamike,^[15][16], čime utiče na brojne puteve prometa koji potiču iz ili prelaze u endosomni sistem na putu do trans-Golgijeve mreže ili kasnijih odjeljaka duž endocitoznog puta.^{[17][18][19][20][21][22]}

Medicinski značaj

PIKfyve mutacije koje pogađaju jedan od dva PIKFYVE alela pronađene su u 8 od 10 porodica sa Francois-Neetens distrofija rožnjačine fleke. Poremećaj oba PIKFYVE alela kod miša je smrtonosan u fazi predimplantacijskog embriona. Uloga PIKfyve u invaziji patogena utvrđena je dokazima iz ćelijskih studija koje impliciraju aktivnost PIKfyve u replikaciji HIV-a i bakterija]] roda Salmonella. Na vezu PIKfyve-a sa dijabetesom tipa 2 upućuju zapažanja da PIKfyve perturbacije inhibiraju unos glukoze reguliran insulinom.^[23][24] Sukladno tome, miševi sa selektivnim poremećajem gena Pikfyve u skeletnim mišićima, tkivo koje je uglavnom odgovorno za smanjenje šećera u krvi nakon jela, ispoljavajući sistemsku otpornost na insulin, netoleranciju glukoze, hiperinsulinemiju i povećanu adipoznost, tj. tipske simptome za predijabetes.^[25]

Inhibitori PIKfyve-a kao potencijalni antikancerski lijekovi

Nekoliko inhibitora PIKfyve-ovih malih molekula pokazalo se obećavajućim kao terapija za rak u pretkliničkim studijama, zbog selektivne toksičnosti u B-ćelijama ne-Hodgkinovog limfoma.^[26] or in U-251 glioblastoma cells.^[27] Inhibitori PIKfyve-a uzrokuju ćelijsku smrt i u ćelijama melanoma A-375, koje za rast i proliferaciju ovise o autofagiji, uslijed oštećene homeostaze lizozoma.^[14]

Ove interakcije povezuju PIKfyve sa na mikrotubulama baziranim endosomom na trans-Golgijevoj mreži prometa. Pod kontinuiranom aktivacijom glutamatnog receptora, PIKfyve veže se i olakšava razgradnju lizosomskog Ca_v1.2, naponski zavisnog kalcijskog kanal tipa 1.2, štiteći tako neurone od eksitotoksičnosti.^[28] PIKfyve negativno regulira Ca²⁺ ovisnu egzocitozu u neuroendokrinim ćelijama, bez uticaja na naponske kanale.

Evoluciijska biologija

PIKFYVE pripada velikoj porodici evolucijski očuvanih lipidnih kinaza. Geni za pojedinačne kopije kodiraju slično strukturirane fosfoinozitidne kinaze, koje sadrže domen FYVE, postoje u većini genoma, od kvasaca do čovjeka. Biljka Arabidopsis thaliana ima nekoliko kopija tog enzima. Viši eukarioti (prema Drosophila melanogaster), stiču dodatni DEP domen. Enzim Fab1p S. cerevisiae potreban je za sintezu PtdIns (3,5) P2 u baznim uvjetima i kao odgovor na hiperosmotski šok. PtdIns5P, stvoren PIKfyve-om kinaznom aktivnošću u ćelijama sisara, nije otkriven u pupajućem kvascu. Kvasac Fab1p veže se na Vac14p (ortolog ljudskog ArPIKfyve) i Fig4p (ortolog Sac3). Kompleks kvasca Fab1 također uključuje Vac7p i vjerovatno Atg18p, proteine koji nisu otkriveni u PIKfyve-u sisarskog kompleksa.^[5] S. cerevisiae mogao bi preživjeti bez Fab1. Nasuprot tome, nokaut enzima koji sadrže domen FYVE u A. thaliana, D. melanogaster, C. elegans i M. musculus dovodi do smrtnosti embriona, što ukazuje da su fosfoinozitidne kinaze koje sadrže domen FYVE postale ključne u embrionskom razvoju višećelijskih organizama.^{[29][30][31][32]} Tako, tokom evolucije, fosfoinozitidne kinaze koje sadrže FYVE domen zadržavaju nekoliko aspekata strukturne organizacije, enzimske aktivnosti i interakcija proteina iz pupajućeg kvasca. Kod viših eukariota, enzimi stiču jedan dodatni domen, sa ulogom u proizvodnji PtdIns5P, nove grupe interaktivnih proteina i postaju bitni u razvoju embriona.^[5]

Reference

1. GRCh38: Ensembl release 89: ENSG00000115020 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025949 - Ensembl, maj 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. 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.
7. Sbrissa D, Ikonomov OC, Deeb R, Shisheva A (decembar 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.
8. 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.
9. Zolov SN, Bridges D, Zhang Y, Lee WW, Riehle E, Verma R, et al. (oktobar 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. doi:10.1073/pnas.1203106109. PMC 3491506. PMID 23047693.
10. Shisheva A, Sbrissa D, Ikonomov O (januar 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.
11. Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, et al. (decembar 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.
12. 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.
13. Sbrissa D, Ikonomov OC, Shisheva A (februar 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.
14. Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, et al. (februar 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.
15. 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.
16. 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.
17. Ikonomov OC, Sbrissa D, Shisheva A (juli 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.
18. Ikonomov OC, Sbrissa D, Mlak K, Deeb R, Fligger J, Soans A, et al. (decembar 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.
19. Rutherford AC, Traer C, Wassmer T, Pattni K, Bujny MV, Carlton JG, et al. (oktobar 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.
20. Jefferies HB, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, et al. (februar 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.
21. Shisheva A (juni 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.
22. Ikonomov OC, Fligger J, Sbrissa D, Dondapati R, Mlak K, Deeb R, Shisheva A (februar 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.
23. Ikonomov OC, Sbrissa D, Mlak K, Shisheva A (decembar 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 (juli 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.
25. 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.
26. 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.
27. 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.
28. Tsuruta F, Green EM, Rousset M, Dolmetsch RE (oktobar 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.
29. 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.
30. Rusten TE, Rodahl LM, Pattni K, Englund C, Samakovlis C, Dove S, et al. (septembar 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.
31. Nicot AS, Fares H, Payrastre B, Chisholm AD, Labouesse M, Laporte J (juli 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.
32. Whitley P, Hinz S, Doughty J (decembar 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.

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