Phosphatidylinositol 5-phosphate

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.[1]

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).[2] Notably, steady-state PtdIns5P levels are more than 5-fold higher than those of PtdIns(3,5)P2.[3][4]

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).[5] In many cell types, however, PtdIns5P is not detected by HPLC due to technical limitations associated with its poor separation from the abundant PtdIns4P.[6] 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.[7]

Based on studies with the mass assay[6] and an improved HPLC technique,[8] 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.[9] The cytoplasmic and nuclear pools have distinct functions and regulation.[10]

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,[11][12] as well as by [PIP5K]s.[13] 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)[6][14] and PIKfyve silencing by small interfering RNAs.[15] 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. [3]

Likewise, similar reduction of PtdIns5P and PtdIns(3,5)P2 is found in fibroblasts with knockout of the PIKfyve activator[16] ArPIKfyve/VAC14.[4] 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. [17] Concordantly, genetic ablation of the myotubularin-related protein 2 (MTMR2) causes elevation of cellular PtdIns(3,5)P2 and a decrease of PtdIns5P.[18] 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.[19] Noteworthy, the PIKfyve complex underlies both PtdIns(3,5)P2 synthesis from and turnover to PtdIns3P. [20] 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[21] and two mammalian phosphatases – PtdIns(4,5)P2 4-phosphatase type I and type II.[22]

Currently, there is no known mammalian phosphatase to specifically dephosphorylate PtdIns5P. The pathway for PtdIns5P clearance involves synthesis of PtdIns(4,5)P2.[10]

Functions

The levels of PtdIns5P change significantly in response to physiological and pathological stimuli. Insulin,[8][23] thrombin,[7] T-cell activation,[24] and cell transformation with nucleophosmin anaplastic lymphoma tyrosine kinase (NPM-ALK),[15] cause elevation of cellular PtdIns5P levels. In contrast, hypoosmotic shock[6] and histamine treatment[25] decrease the levels of PtdIns5P. In T-cells, two “downstream of tyrosine kinase” proteins DOK1 and DOK2 are proposed as PtdIns5P-binding proteins and effectors.[24]

As the other phosphoinositides, PtdIns5P is also present in the nucleus of mammalian cells.[26] The nuclear PtdIns5P pool is controlled by the nuclear type I PtdIns(4,5)P2 4-phosphatase that, in conjunction with the PIPKIIbeta kinase, plays a role in UV stress, apoptosis and cell cycle progression.[9][27][28]

The function of PtdIns5P in nuclear signaling likely involves ING2, a member of the ING family. The proteins of this family associate with and modulate the activity of histone acetylases and deacetylases as well as induce apoptosis through p53 acetylation. The ING2 interacts with PtdIns5P via its plant homeodomain (PHD) finger motif. [29]

In summary, the available evidence indicates that PIKfyve activity is the major source of steady-state cellular PtdIns5P. Under certain conditions, PtdIns5P is produced by dephosphorylation of bis-phosphoinositides. PtdIns5P is involved in regulation of both basic cellular functions and responses to a multitude of physiological and pathological stimuli by yet- to- be specified molecular mechanisms.

References

  1. ↑ Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112):651-7. PMID 17035995
  2. ↑ Shisheva A. Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases. Front Biosci. 2003 Sep 1;8:s945-6. Review. PMID 12957825
  3. 1 2 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
  4. 1 2 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
  5. ↑ 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
  6. 1 2 3 4 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
  7. 1 2 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
  8. 1 2 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
  9. 1 2 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
  10. 1 2 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
  11. ↑ 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
  12. ↑ 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.
  13. ↑ 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
  14. ↑ Shisheva A. PIKfyve: Partners, significance, debates and paradoxes. Cell Biol Int. 2008 Jun;32(6):591-604. Epub 2008 Jan 25. Review.PMID 18304842
  15. 1 2 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ Sbrissa D, Ikonomov OC, Strakova J, Shisheva A. Role for a novel signaling intermediate, phosphatidylinositol 5-phosphate, in insulin-regulated F-actin stress fiber breakdown and GLUT4 translocation. Endocrinology. 2004 Nov;145(11):4853-65. Epub 2004 Jul 29. PMID 15284192.
  24. 1 2 Guittard G, Gérard A, Dupuis-Coronas S, Tronchère H, Mortier E, Favre C, Olive D, Zimmermann P, Payrastre B, Nunès JA. Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells. J Immunol. 2009 Apr 1;182(7):3974-8. PMID 19299694
  25. ↑ Roberts HF, Clarke JH, Letcher AJ, Irvine RF, Hinchliffe KA. Effects of lipid kinase expression and cellular stimuli on phosphatidylinositol 5-phosphate levels in mammalian cell lines. FEBS Lett. 2005 May 23;579(13):2868-72. PMID 15876433
  26. ↑ Barlow CA, Laishram RS, Anderson RA. Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol. 2010 Jan;20(1):25-35. Epub 2009 Oct 19. PMID 19846310.
  27. ↑ Clarke JH, Letcher AJ, D'santos CS, Halstead JR, Irvine RF, Divecha N. Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells. Biochem J. 2001 Aug 1;357(Pt 3):905-10. PMID 11463365
  28. ↑ Jones DR, Bultsma Y, Keune WJ, Halstead JR, Elouarrat D, Mohammed S, Heck AJ, D'Santos CS, Divecha N. Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell. 2006 Sep 1;23(5):685-95. PMID 16949365
  29. ↑ Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J. The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell. 2003 Jul 11;114(1):99-111. PMID 12859901
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