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Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.〔Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112):651-7. PMID 17035995〕 Phosphatidylinositol 5-phosphate is one of the 7 known cellular phosphoinositides with less understood functions. It is phosphorylated on position D-5 of the inositol head group, which is attached via phosphodiester linkage to diacylglycerol (with varying chemical composition of the acyl chains, frequently 1-stearoyl-2-arachidonoyl chain). In quiescent cells, on average, PtdIns5P is of similar or higher abundance as compared to PtdIns3P and ~20-100-fold below the levels of PtdIns4P (Phosphatidylinositol 4-phosphate and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate).〔Shisheva A. Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases. Front Biosci. 2003 Sep 1;8:s945-6. Review. PMID 12957825〕 Notably, steady-state PtdIns5P levels are more than 5-fold higher than those of PtdIns(3,5)P2.〔Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A. The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. J Biol Chem. 2011 Apr 15;286(15):13404-13. Epub 2011 Feb 24. PMID 21349843〕〔Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, WeismanLS. Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17518-23. Epub 2007 Oct 23. PMID 17956977〕 PtdIns5P was first demonstrated by HPLC (high pressure liquid chromatography) in mouse fibroblasts as a substrate for PtdIns(4,5)P2 synthesis by type II PIP kinases (1-phosphatidylinositol-5-phosphate 4-kinase).〔Rameh LE, Tolias K, Duckworth BC, Cantley LC. A new pathway for synthesis of phosphatydilinositol-4,5-bisphosphate. Nature. 1997 Nov 13;390(6656):192-6. PMID 9367159〕 In many cell types, however, PtdIns5P is not detected by HPLC due to technical limitations associated with its poor separation from the abundant PtdIns4P.〔Sbrissa D, Ikonomov OC, Deeb R, Shisheva A. Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells. J Biol Chem. 2002 Dec 6;277(49):47276-84. Epub 2002 Sep 20. PMID 12270933〕 Rather, PtdIns5P is measured by the "mass assay", where PtdIns5P (as a part of the extracted cellular lipids) is converted in vitro by purified PtdIns5P 4-kinase to PtdIns(4,5)P2 that is subsequently quantified.〔Morris JB, Hinchliffe KA, Ciruela A, Letcher AJ, Irvine RF. Thrombin stimulation of platelets causes an increase in phosphatydilinositol 5-phosphate revealed by mass assay. FEBS Lett. 2000 Jun 9;475(1):57-60. PMID 10854858〕 Based on studies with the mass assay〔 and an improved HPLC technique,〔Sarkes D, Rameh LE. A novel HPLC-based approach makes possible the spatial characterization of cellular PtdIns5P and other phosphoinositides. Biochem J. 2010 May 27;428(3):375-84. PMID 20370717〕 PtdIns5P is detected in all studied mammalian cells. Most of the cellular PtdIns5P is found on cytoplasmic membranes whereas a smaller fraction resides in the nucleus.〔Zou J, Marjanovic J, Kisseleva MV, Wilson M, Majerus PW. Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16834-9. Epub 2007 Oct 16. PMID 17940011〕 The cytoplasmic and nuclear pools have distinct functions and regulation.〔Grainger DL, Tavelis C, Ryan AJ, Hinchliffe KA. The emerging role of PtdIns5P: another signalling phosphoinositide takes its place. Biochem Soc Trans. 2012 Feb 1;40(1):257-61. PMID 22260701〕 ==Metabolism== Cellular PtdIns5P could be produced by D-5-phosphorylation of phosphatidylinositol or by dephosphorylation of PtdIns(3,5P)2 or PtdIns(4,5)P2. Interestingly, each of these possibilities is experimentally supported. PtdIns5P is synthesized in vitro by PIKfyve, an enzyme principally responsible for PtdIns(3,5)P2 production,〔Sbrissa D, Ikonomov OC, Shisheva A. PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin. J Biol Chem. 1999 Jul 30;274(31):21589-97. PMID 10419465〕〔Shisheva A. PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2). Cell Biol Int. 2001;25(12):1201-6. PMID 11748912.〕 as well as by ()s.〔Tolias KF, Rameh LE, Ishihara H, Shibasaki Y, Chen J, Prestwich GD, Cantley LC, Carpenter CL. Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate. J Biol Chem. 1998 Jul 17;273(29):18040-6. PMID 9660759〕 A major role for PIKfyve in synthesis of cellular PtdIns5P is suggested by data for reduced PtdIns5P mass levels upon heterologous overexpression of the enzymatically inactive PIKfyve point-mutant (PIKfyveK1831E)〔〔Shisheva A. PIKfyve: Partners, significance, debates and paradoxes. Cell Biol Int. 2008 Jun;32(6):591-604. Epub 2008 Jan 25. Review.PMID 18304842〕 and PIKfyve silencing by small interfering RNAs.〔Coronas S, Lagarrigue F, Ramel D, Chicanne G, Delsol G, Payrastre B, Tronchère H. Elevated levels of PtdIns5P in NPM-ALK transformed cells: implication of PIKfyve. Biochem Biophys Res Commun. 2008 Jul 25;372(2):351-5. Epub 2008 May 22. PMID 18501703〕 Such a role is reinforced by data in transgenic fibroblasts with one genetically disrupted PIKfyve allele, demonstrating equal reduction of steady-state levels of PtdIns5P and PtdIns(3,5)P2. 〔 Likewise, similar reduction of PtdIns5P and PtdIns(3,5)P2 is found in fibroblasts with knockout of the PIKfyve activator〔Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A. A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity. Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A. Mol Cell Biol. 2004 Dec;24(23):10437-47.PMID 15542851〕 ArPIKfyve/VAC14.〔 This experimental evidence coupled with the fact that the cellular levels of PtdIns5P exceed more than 5-fold those of PtdIns(3,5)P2 indicate a predominant role of PIKfyve in maintenance of the steady-state PtdIns5P levels via D-5 phosphorylation of phosphatidylinositol. A role for the myotubularin protein family in PtdIns5P production has been proposed based on dephosphorylation of PtdIns(3,5)P2 by overexpressed myotubularin 1. 〔Tronchère H, Laporte J, Pendaries C, Chaussade C, Liaubet L, Pirola L, Mandel JL, Payrastre B. Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells. J Biol Chem. 2004 Feb 20;279(8):7304-12. Epub 2003 Dec 1. PMID 14660569〕 Concordantly, genetic ablation of the myotubularin-related protein 2 (MTMR2) causes elevation of cellular PtdIns(3,5)P2 and a decrease of PtdIns5P.〔Vaccari I, Dina G, Tronchère H, Kaufman E, Chicanne G, Cerri F, Wrabetz L, Payrastre B, Quattrini A, Weisman LS, Meisler MH, Bolino A. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 2011 Oct;7(10):e1002319. Epub 2011 Oct 20. PMID 22028665〕 The low cellular levels of PtdIns(3,5)P2 suggest that myotubularin phosphatase activity plays a minor role in maintaining the steady-state PtdIns5P levels. Importantly, PtdIns(3,5)P2 is synthesized from PtdIns3P by the PIKfyve complex that includes ArPIKfyve and Sac3/Fig4.〔Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A. 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. 2007 Aug 17;282(33):23878-91. Epub 2007 Jun 7. PMID 17556371〕 Noteworthy, the PIKfyve complex underlies both PtdIns(3,5)P2 synthesis from and turnover to PtdIns3P. 〔Ikonomov OC, Sbrissa D, Fenner H, Shisheva A. PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis. J Biol Chem. 2009 Dec 18;284(51):35794-806. PMID 19840946〕 The relative proportion of PtdIns(3,5)P2 turnover by myotubularin phosphatases versus that by Sac3 is unknown. PtdIns5P can also be produced by dephosphorylation of PtdIns(4,5)P2. Such phosphatase activity is shown for Shigella flexneri effector IpgD〔Niebuhr K, Giuriato S, Pedron T, Philpott DJ, Gaits F, Sable J, Sheetz MP, Parsot C, Sansonetti PJ, Payrastre B. Conversion of PtdIns(4,5)P(2) into PtdIns(5)P by the S.flexneri effector IpgD reorganizes host cell morphology. EMBO J. 2002 Oct 1;21(19):5069-78. PMID 12356723〕 and two mammalian phosphatases – PtdIns(4,5)P2 4-phosphatase type I and type II.〔Ungewickell A, Hugge C, Kisseleva M, Chang SC, Zou J, Feng Y, Galyov EE, Wilson M, Majerus PW. The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18854-9. Epub 2005 Dec 19. PMID 16365287〕 Currently, there is no known mammalian phosphatase to specifically dephosphorylate PtdIns5P. The pathway for PtdIns5P clearance involves synthesis of PtdIns(4,5)P2.〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Phosphatidylinositol 5-phosphate」の詳細全文を読む スポンサード リンク
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