A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate (original) (raw)

Nature volume 390, pages 192–196 (1997)Cite this article

Abstract

Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the _D_-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities1. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the _D_-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the _D_-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K. The earlier error in characterizing the activity of the type II enzyme is due to the presence of contaminating PtdIns-5-P in commercial preparations of PtdIns-4-P. Although PtdIns-5-P was previously thought not to exist in vivo, we find evidence for the presence of this lipid in mammalian fibroblasts, establishing a new pathway for PtdIns-4,5-P2 synthesis.

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References

  1. Loijens, J. C., Boronenkov, I. V., Parker, G. J. & Anderson, R. A. The phosphatidylinositol 4-phosphate 5-kinase family. Adv. Enz. Reg. 36, 115–140 (1996).
    Article CAS Google Scholar
  2. Damen, J. E. et al. The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc. Natl Acad. Sci. USA 93, 1689–1693 (1996).
    Article ADS CAS Google Scholar
  3. Meyers, R. & Cantley, L. C. Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase. J. Biol. Chem. 272, 4385–4390 (1997).
    Article Google Scholar
  4. Whiteford, C. C., Brearley, C. A. & Ulug, E. T. Phosphatidylinositol 3,5-bisphosphate defines a novel PI 3-kinase pathway in resting mouse fibroblasts. Biochem. J. 323, 597–601 (1997).
    Article CAS Google Scholar
  5. Ling, L. E., Schulz, J. T. & Cantley, L. C. Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells. J. Biol. Chem. 264, 5080–5088 (1989).
    CAS PubMed Google Scholar
  6. Bazenet, C. E., Ruano, A. R., Brockman, J. L. & Anderson, R. A. The human erythrocyte contains two forms of phosphatidylinositol-4-phosphate 5-kinase which are differentially active toward membranes. J. Biol. Chem. 265, 18012–18022 (1990).
    CAS PubMed Google Scholar
  7. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. & Cantley, L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167–175 (1989).
    Article CAS Google Scholar
  8. Carpender, C. L. & Cantley, L. C. Phosphoinositide kinases. Biochemistry 29, 11147–11156 (1990).
    Article Google Scholar
  9. Boronenkov, I. V. & Anderson, R. A. The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases. J. Biol. Chem. 270, 2881–2884 (1995).
    Article CAS Google Scholar
  10. Divecha, N., Truong, O., Hsuan, J. J., Hinchcliffe, K. A. & Irvine, R. F. The cloning and sequence of the C isoform of PtdIns4P 5-kinase. Biochem. J. 309, 715–719 (1995).
    Article CAS Google Scholar
  11. Hinchliffe, K. A., Irvine, R. F. & Divecha, N. Aggregation-dependent, integrin-mediated increases in cytoskeletally associated PtdInsP2(4,5) levels in human platelets are controlled by translocation of PtdIns 4-P 5-kinase C to the cytoskeleton. EMBO J. 15, 6516–6524 (1996).
    Article CAS Google Scholar
  12. Castellino, A. M., Parker, G. J., Boronenkov, I. V., Anderson, R. A. & Chao, M. V. Anovel interaction between the juxtamembrane region of the p55 tumor necrosis factor receptor and phosphatidylinositol-4-phosphate 5-kinase. J. Biol. Chem. 272, 5861–5870 (1997).
    Article CAS Google Scholar
  13. Zhang, X. et al. Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules. J. Biol. Chem. 272, 17756–17761 (1997).
    Article CAS Google Scholar
  14. Yamamoto, K., Graziani, A., Carpenter, C., Cantley, L. C. & Lapetina, E. G. Anovel pathway for the formation of phosphatidylinositol 3,4-bisphosphate. Phosphorylation of phosphatidylinositol 3-monophosphate by phosphatidylinositol-3-monophosphate 4-kinase. J. Biol. Chem. 265, 22086–22089 (1990).
    CAS PubMed Google Scholar
  15. Yamamoto, K. & Lapetina, E. G. Protein kinase C-mediated formation of phosphatidylinositol 3,4-bisphosphate in human platelets. Biochem. Biophys. Res. Commun. 168, 466–472 (1990).
    Article CAS Google Scholar
  16. Graziani, A., Ling, L. E., Endemann, G., Carpenter, C. L. & Cantley, L. C. Purification and characterization of human erythrocyte phosphatidylinositol 4-kinase. Phosphatidylinositol 4-kinase and phosphatidylinositol 3-monophosphate 4-kinase are distinct enzymes. Biochem. J. 284, 39–45 (1992).
    Article CAS Google Scholar
  17. Ishihara, H. et al. Cloning of cDNAs encoding two isoforms of 68-kDa type I phosphatidylinositol-4-phosphate 5-kinase. J. Biol. Chem. 271, 23611–23614 (1996).
    Article CAS Google Scholar
  18. Serunian, L. A., Auger, K. R. & Cantley, L. C. Identiffication and quantiffication of polyphosphoinositides produced in response to platelet-derived growth factor stimulation. Meth. Enzymol. 198, 78–87 (1991).
    Article CAS Google Scholar

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Acknowledgements

We thank G. Preswich for synthetic PtdIns-5-P, K. Hinchliffe for recombinant type II PIPK, H. Ishihara for type I PIPK cDNA, K. Ravinchandran for the GST-SHIP expression vector, R. Meyers for recombinant PI-4Kβ, A. Couvillon for preparing recombinant type I PIPK and recombinant PI-3K, and D. Fruman and C. Carpenter for critically reading this manuscript, L.E.R. is supported by The Medical Foundation–Charles King Trust. This research was supported by the NIH.

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Authors and Affiliations

  1. Department of Cell Biology, and Division of Signal Transduction, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, 02115, Massachusetts, USA
    Lucia E. Rameh, Kimberley F. Tolias, Brian C. Duckworth & Lewis C. Cantley

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  1. Lucia E. Rameh
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  2. Kimberley F. Tolias
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  3. Brian C. Duckworth
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  4. Lewis C. Cantley
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Correspondence toLucia E. Rameh.

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Rameh, L., Tolias, K., Duckworth, B. et al. A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.Nature 390, 192–196 (1997). https://doi.org/10.1038/36621

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