Jump to content

Phosphatidylinositol 5-phosphate

From Wikipedia, the free encyclopedia

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

[edit]

Cellular PtdIns5P could be produced by D-5-phosphorylation of phosphatidylinositol or by dephosphorylation of PtdIns(3,5)P2 or PtdIns(4,5)P2. 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]

In myoblast, PtdIns5P is rapidly metabolized by the PI5P 4-kinase α into PI(4,5)P2 which accumulates at the plasma membrane thereby facilitating the formation of podosome-like protrusions, playing a crucial role in the spatiotemporal regulation of myoblast fusion.[23]

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

[edit]

The levels of PtdIns5P change significantly in response to physiological and pathological stimuli. Insulin,[8][24] thrombin,[7] T-cell activation,[25] 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[26] 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.[25]

As the other phosphoinositides, PtdIns5P is also present in the nucleus of mammalian cells.[27] 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][28][29]

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. [30]

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

[edit]
  1. ^ Di Paolo, Gilbert; De Camilli, Pietro (2006-10-12). "Phosphoinositides in cell regulation and membrane dynamics". Nature. 443 (7112): 651–657. Bibcode:2006Natur.443..651D. doi:10.1038/nature05185. ISSN 1476-4687. PMID 17035995. S2CID 10479545.
  2. ^ Shisheva, Assia (2003-09-01). "Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases". Frontiers in Bioscience: A Journal and Virtual Library. 8 (6): s945–946. doi:10.2741/1101. ISSN 1093-9946. PMID 12957825.
  3. ^ a b Ikonomov, Ognian C.; Sbrissa, Diego; Delvecchio, Khortnal; et al. (2011-04-15). "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): 13404–13413. doi:10.1074/jbc.M111.222364. ISSN 1083-351X. PMC 3075686. PMID 21349843.
  4. ^ a b Zhang, Yanling; Zolov, Sergey N.; Chow, Clement Y.; et al. (2007-10-30). "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice". Proceedings of the National Academy of Sciences of the United States of America. 104 (44): 17518–17523. Bibcode:2007PNAS..10417518Z. doi:10.1073/pnas.0702275104. ISSN 0027-8424. PMC 2077288. PMID 17956977.
  5. ^ Rameh, L. E.; Tolias, K. F.; Duckworth, B. C.; Cantley, L. C. (1997-11-13). "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate". Nature. 390 (6656): 192–196. Bibcode:1997Natur.390..192R. doi:10.1038/36621. ISSN 0028-0836. PMID 9367159. S2CID 4403301.
  6. ^ a b c d Sbrissa, Diego; Ikonomov, Ognian C.; Deeb, Robert; Shisheva, Assia (2002-12-06). "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): 47276–47284. doi:10.1074/jbc.M207576200. ISSN 0021-9258. PMID 12270933.
  7. ^ a b Morris, J. B.; Hinchliffe, K. A.; Ciruela, A.; et al. (2000-06-09). "Thrombin stimulation of platelets causes an increase in phosphatidylinositol 5-phosphate revealed by mass assay". FEBS Letters. 475 (1): 57–60. Bibcode:2000FEBSL.475...57M. doi:10.1016/s0014-5793(00)01625-2. ISSN 0014-5793. PMID 10854858. S2CID 41475679.
  8. ^ a b Sarkes, Deborah; Rameh, Lucia E. (2010-05-27). "A novel HPLC-based approach makes possible the spatial characterization of cellular PtdIns5P and other phosphoinositides". The Biochemical Journal. 428 (3): 375–384. doi:10.1042/BJ20100129. ISSN 1470-8728. PMC 2944655. PMID 20370717.
  9. ^ a b Zou, Jun; Marjanovic, Jasna; Kisseleva, Marina V.; et al. (2007-10-23). "Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 104 (43): 16834–16839. Bibcode:2007PNAS..10416834Z. doi:10.1073/pnas.0708189104. ISSN 0027-8424. PMC 2040409. PMID 17940011.
  10. ^ a b Grainger, Deborah L.; Tavelis, Christodoulos; Ryan, Alexander J.; Hinchliffe, Katherine A. (2012). "The emerging role of PtdIns5P: another signalling phosphoinositide takes its place". Biochemical Society Transactions. 40 (1): 257–261. doi:10.1042/BST20110617. ISSN 1470-8752. PMID 22260701.
  11. ^ Sbrissa, D.; Ikonomov, O. C.; Shisheva, A. (1999-07-30). "PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin". The Journal of Biological Chemistry. 274 (31): 21589–21597. doi:10.1074/jbc.274.31.21589. ISSN 0021-9258. PMID 10419465.
  12. ^ Shisheva, A. (2001). "PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2)". Cell Biology International. 25 (12): 1201–1206. doi:10.1006/cbir.2001.0803. ISSN 1065-6995. PMID 11748912. S2CID 29411107.
  13. ^ Tolias, K. F.; Rameh, L. E.; Ishihara, H.; et al. (1998-07-17). "Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate". The Journal of Biological Chemistry. 273 (29): 18040–18046. doi:10.1074/jbc.273.29.18040. ISSN 0021-9258. PMID 9660759.
  14. ^ Shisheva, Assia (2008). "PIKfyve: Partners, significance, debates and paradoxes". Cell Biology International. 32 (6): 591–604. doi:10.1016/j.cellbi.2008.01.006. ISSN 1065-6995. PMC 2491398. PMID 18304842.
  15. ^ a b Coronas, S.; Lagarrigue, F.; Ramel, D.; et al. (2008-07-25). "Elevated levels of PtdIns5P in NPM-ALK transformed cells: implication of PIKfyve". Biochemical and Biophysical Research Communications. 372 (2): 351–355. doi:10.1016/j.bbrc.2008.05.062. ISSN 1090-2104. PMID 18501703.
  16. ^ Sbrissa, Diego; Ikonomov, Ognian C.; Strakova, Jana; et al. (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): 10437–10447. doi:10.1128/MCB.24.23.10437-10447.2004. ISSN 0270-7306. PMC 529046. PMID 15542851.
  17. ^ Tronchère, Hélène; Laporte, Jocelyn; Pendaries, Caroline; et al. (2004-02-20). "Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells". The Journal of Biological Chemistry. 279 (8): 7304–7312. doi:10.1074/jbc.M311071200. ISSN 0021-9258. PMID 14660569.
  18. ^ Vaccari, Ilaria; Dina, Giorgia; Tronchère, Hélène; et al. (2011). "Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies". PLOS Genetics. 7 (10): e1002319. doi:10.1371/journal.pgen.1002319. ISSN 1553-7404. PMC 3197679. PMID 22028665.
  19. ^ Sbrissa, Diego; Ikonomov, Ognian C.; Fu, Zhiyao; et al. (2007-08-17). "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): 23878–23891. doi:10.1074/jbc.M611678200. ISSN 0021-9258. PMID 17556371.
  20. ^ Ikonomov, Ognian C.; Sbrissa, Diego; Fenner, Homer; Shisheva, Assia (2009-12-18). "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): 35794–35806. doi:10.1074/jbc.M109.037515. ISSN 1083-351X. PMC 2791009. PMID 19840946.
  21. ^ Niebuhr, Kirsten; Giuriato, Sylvie; Pedron, Thierry; et al. (2002-10-01). "Conversion of PtdIns(4,5)P(2) into PtdIns(5)P by the S.flexneri effector IpgD reorganizes host cell morphology". The EMBO Journal. 21 (19): 5069–5078. doi:10.1093/emboj/cdf522. ISSN 0261-4189. PMC 129044. PMID 12356723.
  22. ^ Ungewickell, Alexander; Hugge, Christopher; Kisseleva, Marina; et al. (2005-12-27). "The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases". Proceedings of the National Academy of Sciences of the United States of America. 102 (52): 18854–18859. Bibcode:2005PNAS..10218854U. doi:10.1073/pnas.0509740102. ISSN 0027-8424. PMC 1323219. PMID 16365287.
  23. ^ Mansat, Mélanie; Kpotor, Afi Oportune; Chicanne, Gaëtan; et al. (2024-06-04). "MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion". Proc. Natl. Acad. Sci. U.S.A. doi:10.1073/pnas.2217971121. PMC 11161799. PMID 38805272.
  24. ^ Sbrissa, Diego; Ikonomov, Ognian C.; Strakova, Jana; Shisheva, Assia (2004). "Role for a novel signaling intermediate, phosphatidylinositol 5-phosphate, in insulin-regulated F-actin stress fiber breakdown and GLUT4 translocation". Endocrinology. 145 (11): 4853–4865. doi:10.1210/en.2004-0489. ISSN 0013-7227. PMID 15284192.
  25. ^ a b Guittard, Geoffrey; Gérard, Audrey; Dupuis-Coronas, Sophie; et al. (2009-04-01). "Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells". Journal of Immunology. 182 (7): 3974–3978. doi:10.4049/jimmunol.0804172. ISSN 1550-6606. PMID 19299694.
  26. ^ Roberts, Hilary F.; Clarke, Jonathan H.; Letcher, Andrew J.; et al. (2005-05-23). "Effects of lipid kinase expression and cellular stimuli on phosphatidylinositol 5-phosphate levels in mammalian cell lines". FEBS Letters. 579 (13): 2868–2872. Bibcode:2005FEBSL.579.2868R. doi:10.1016/j.febslet.2005.04.027. ISSN 0014-5793. PMID 15876433.
  27. ^ Barlow, Christy A.; Laishram, Rakesh S.; Anderson, Richard A. (2010). "Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum". Trends in Cell Biology. 20 (1): 25–35. doi:10.1016/j.tcb.2009.09.009. ISSN 1879-3088. PMC 2818233. PMID 19846310.
  28. ^ Clarke, J. H.; Letcher, A. J.; D'santos, C. S.; et al. (2001-08-01). "Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells". The Biochemical Journal. 357 (Pt 3): 905–910. doi:10.1042/0264-6021:3570905. ISSN 0264-6021. PMC 1222024. PMID 11463365.
  29. ^ Jones, David R.; Bultsma, Yvette; Keune, Willem-Jan; et al. (2006-09-01). "Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta". Molecular Cell. 23 (5): 685–695. doi:10.1016/j.molcel.2006.07.014. ISSN 1097-2765. PMID 16949365.
  30. ^ Gozani, Or; Karuman, Philip; Jones, David R.; et al. (2003-07-11). "The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor". Cell. 114 (1): 99–111. doi:10.1016/s0092-8674(03)00480-x. ISSN 0092-8674. PMID 12859901.