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  • Review Article
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Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Nature Reviews Immunology volume 10, pages 257–271 (2010)Cite this article

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Key Points

  • By functioning as a soluble analogue of the membrane lipid phosphatidylinositol-3,4,5-trisphosphate (here termed PtdInsP3), inositol-1,3,4,5-tetrakisphosphate (here termed InsP4) can control the functions of phosphoinositide 3-kinases (PI3Ks), phosphatase and tensin homologue (PTEN), SH2-domain-containing inositol-5-phosphatase 1 (SHIP1) and SHIP2 — the kinases that produce and the phosphatases that metabolize PtdInsP3 in lymphocytes. InsP4 probably has additional functions that might include those of the many InsP4 derivatives. In the best understood mechanism so far, InsP4 regulates the membrane recruitment of proteins by promoting or inhibiting the interactions of their pleckstrin-homology (PH) domains with PtdInsP3.

  • In mouse thymocytes, positive regulation of inducible T cell kinase (ITK) membrane recruitment by InsP4 establishes a feedback loop of phospholipase Cγ1 activation downstream of the T cell receptor that is essential for the production of sufficient amounts of the second messenger lipid diacylglycerol to trigger positive selection and the generation of a mature T cell repertoire. These findings identified the first physiological function of InsP4 as an essential soluble messenger molecule, two decades after its original discovery.

  • Unexpectedly, defective function of the InsP4-producing kinase ITPKC in humans might result in peripheral T cell hyperactivation and contribute to Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries.

  • The InsP4-producing kinase ITPKB is required for B cell development and functional competence, as shown by the B cell developmental defects and anergy in Itpkb−/− mice. The mechanisms through which ITPKB controls B cell development are unclear but might include inhibition of store-operated Ca2+ entry (SOCE) by InsP4 through an as yet unknown mechanism.

  • ITPKB limits SOCE and PtdInsP3-mediated membrane recruitment of the PI3K effector kinase AKT in neutrophils. Defects in these processes and in the production of opsonizing IgG by B cells probably underlie a complex phenotype of increased neutrophil chemotaxis and superoxide production, but decreased neutrophil viability and bacterial clearance, in an acute peritonitis model in Itpkb−/− mice.

  • As key regulators of PI3K function with essential roles in the adaptive and innate immune system and unique structural features that facilitate the development of selective inhibitors, the InsP4-producing ITPKs are attractive targets for the development of novel anti-inflammatory therapies, improved vaccination strategies or methods to overcome immunodeficiencies. However, more detailed studies in relevant disease models and with proof-of-concept small molecule inhibitors are required to establish indications, evaluate potential side effects and address toxicity concerns.

Abstract

The membrane lipid phosphatidylinositol-3,4,5-trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential roles for the soluble PtdInsP3 analogue inositol-1,3,4,5-tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in leukocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

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Figure 1: InsP4 regulates PtdInsP3 function in leukocytes.
Figure 2: InsP4 functions in T cell receptor signalling.
Figure 3: InsP4 functions in B cell receptor signalling.
Figure 4: InsP4 controls haematopoiesis at many levels.

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References

  1. York, J. D. Regulation of nuclear processes by inositol polyphosphates. Biochim. Biophys. Acta 1761, 552–559 (2006).

    CAS  PubMed  Google Scholar 

  2. Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006). This notable review proposed a unified standard nomenclature for inositol phosphates.

    CAS  PubMed  Google Scholar 

  3. Streb, H., Irvine, R. F., Berridge, M. J. & Schulz, I. Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306, 67–69 (1983). This seminal publication first described that Ins(1,4,5)P 3 functions as a second messenger that mediates Ca2+ release in mammalian cells.

    CAS  PubMed  Google Scholar 

  4. Skwarek, L. C. & Boulianne, G. L. Great expectations for PIP: phosphoinositides as regulators of signaling during development and disease. Dev. Cell 16, 12–20 (2009).

    CAS  PubMed  Google Scholar 

  5. Fruman, D. A. & Bismuth, G. Fine tuning the immune response with PI3K. Immunol. Rev. 228, 253–272 (2009).

    CAS  PubMed  Google Scholar 

  6. Buitenhuis, M. & Coffer, P. J. The role of the PI3K–PKB signaling module in regulation of hematopoiesis. Cell Cycle 8, 560–566 (2009).

    CAS  PubMed  Google Scholar 

  7. Rommel, C., Camps, M. & Ji, H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nature Rev. Immunol. 7, 191–201 (2007).

    CAS  Google Scholar 

  8. Hawkins, P. T. & Stephens, L. R. PI3Kγ is a key regulator of inflammatory responses and cardiovascular homeostasis. Science 318, 64–66 (2007).

    CAS  PubMed  Google Scholar 

  9. Weichhart, T. & Saemann, M. D. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann. Rheum. Dis. 67, 70–74 (2008).

    Google Scholar 

  10. Harris, S. J., Parry, R. V., Westwick, J. & Ward, S. G. Phosphoinositide lipid phosphatases: natural regulators of phosphoinositide 3-kinase signaling in T lymphocytes. J. Biol. Chem. 283, 2465–2469 (2008).

    CAS  PubMed  Google Scholar 

  11. Irvine, R. F., Lloyd-Burton, S. M., Yu, J. C., Letcher, A. J. & Schell, M. J. The regulation and function of inositol 1,4,5-trisphosphate 3-kinases. Adv. Enzyme Regul. 46, 314–323 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Pattni, K. & Banting, G. Ins(1,4,5)P3 metabolism and the family of IP3-3Kinases. Cell Signal. 16, 643–654 (2004).

    CAS  PubMed  Google Scholar 

  13. Nalaskowski, M. M. & Mayr, G. W. The families of kinases removing the Ca2+ releasing second messenger Ins(1,4,5)P3 . Curr. Mol. Med. 4, 277–290 (2004).

    CAS  PubMed  Google Scholar 

  14. Schell, M. J. Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling. Cell. Mol. Life Sci. 12 Jan 2010 (doi: 10.1007/s00018-009-0238-0235).

  15. Xia, H. J. & Yang, G. Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations. Cell Res. 15, 83–91 (2005).

    CAS  PubMed  Google Scholar 

  16. Miller, A. T. et al. Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation. Nature Immunol. 8, 514–521 (2007). References 16 and 21 describe the effects of Itpkb deficiency on B cell development and function in a non-BCR-transgenic background. Reference 16 showed that increased BCR-induced SOCE and B cell anergy are key components of the Itpkb−/− mouse phenotype.

    CAS  Google Scholar 

  17. Huang, Y. H. et al. Positive regulation of Itk PH domain function by soluble IP4. Science 316, 886–889 (2007). Reference 17 described the identification of ITK as the first physiological InsP 4 effector. InsP 4 promoted ITK PH domain binding to the membrane-bound lipid PtdInsP 3 , probably through a cooperative allosteric mechanism involving ITK PH domain oligomerization. This is essential for thymocyte positive selection.

    CAS  PubMed  Google Scholar 

  18. Wen, B. G. et al. Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity. Proc. Natl Acad. Sci. USA 101, 5604–5609 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Miller, A. T., Beisner, D. R., Liu, D. & Cooke, M. P. Inositol 1,4,5-trisphosphate 3-kinase B is a negative regulator of BCR signaling that controls B cell selection and tolerance induction. J. Immunol. 182, 4696–4704 (2009). This study follows up on references 16 and 21 and described the effects of Itpkb deficiency on B cell selection in BCR-transgenic mice.

    CAS  PubMed  Google Scholar 

  20. Jia, Y. et al. Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis. Proc. Natl Acad. Sci. USA 105, 4739–4744 (2008). This study showed that Itpkb deficiency results in granulocyte–monocyte progenitor accumulation and increased neutrophil production, probably through mechanisms involving AKT hyperactivation secondary to impaired InsP 4 -mediated inhibition of interactions between the AKT PH domain and PtdInsP 3.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Marechal, Y. et al. Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells. Proc. Natl Acad. Sci. USA 104, 13978–13983 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jia, Y. et al. Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils. Immunity 27, 453–467 (2007). This study described, for the first time, alterations in neutrophil signalling and function in Itpkb−/− mice. The underlying mechanism probably includes impaired InsP 4 -mediated antagonism of AKT PH domain membrane recruitment through PtdIns(3,4,5)P 3 and/or PtdIns(3,4)P 2 binding in neutrophils.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Pouillon, V. et al. Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development. Nature Immunol. 4, 1136–1143 (2003). This study and reference 18 showed that Itpkb deficiency blocks thymocyte positive selection. Both studies showed that TCR-induced Ca2+ mobilization in Itpkb−/− thymocytes is normal. Reference 18 also showed that the block is associated with impaired TCR-induced ERK activation.

    CAS  Google Scholar 

  24. Stokes, A. J. et al. FcɛRI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate. Cell Signal. 18, 640–651 (2006). This publication used results obtained with small molecule ITPK inhibitors to suggest potential functions of ITPKs in mast cells.

    CAS  PubMed  Google Scholar 

  25. Sauer, K., Huang, Y. H., Ying, H., Sandberg, M. & Mayr, G. W. Phosphoinositide analysis in lymphocyte activation. Curr. Protoc. Immunol. 11, 11.1 (2009).

  26. Zhong, X. P., Guo, R., Zhou, H., Liu, C. & Wan, C. K. Diacylglycerol kinases in immune cell function and self-tolerance. Immunol. Rev. 224, 249–264 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Readinger, J. A., Mueller, K. L., Venegas, A. M., Horai, R. & Schwartzberg, P. L. Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk. Immunol. Rev. 228, 93–114 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Prince, A. L., Yin, C. C., Enos, M. E., Felices, M. & Berg, L. J. The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. Immunol. Rev. 228, 115–131 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Feske, S. Calcium signalling in lymphocyte activation and disease. Nature Rev. Immunol. 7, 690–702 (2007).

    CAS  Google Scholar 

  30. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    CAS  PubMed  Google Scholar 

  31. Lemmon, M. A. Membrane recognition by phospholipid-binding domains. Nature Rev. Mol. Cell Biol. 9, 99–111 (2008).

    CAS  Google Scholar 

  32. Juntilla, M. M. & Koretzky, G. A. Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol. Lett. 116, 104–110 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Huang, Y. H., Hoebe, K. & Sauer, K. New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B. Expert Opin. Ther. Targets 12, 391–413 (2008).

    CAS  PubMed  Google Scholar 

  34. Irvine, R. F. Inositide evolution — towards turtle domination? J. Physiol. 566, 295–300 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Otto, J. C. et al. Biochemical analysis of inositol phosphate kinases. Methods Enzymol. 434, 171–185 (2007).

    CAS  PubMed  Google Scholar 

  36. Chang, S. C., Miller, A. L., Feng, Y., Wente, S. R. & Majerus, P. W. The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase. J. Biol. Chem. 277, 43836–43843 (2002).

    CAS  PubMed  Google Scholar 

  37. Saiardi, A. et al. Mammalian inositol polyphosphate multikinase synthesizes inositol 1,4,5-trisphosphate and an inositol pyrophosphate. Proc. Natl Acad. Sci. USA 98, 2306–2311 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nalaskowski, M. M., Deschermeier, C., Fanick, W. & Mayr, G. W. The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization. Biochem. J. 366, 549–556 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Seeds, A. M. & York, J. D. Inositol polyphosphate kinases: regulators of nuclear function. Biochem. Soc. Symp. 74, 183–197 (2007).

    CAS  Google Scholar 

  40. Jun, K. et al. Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice. Learn. Mem. 5, 317–330 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim, I. H. et al. Inositol 1,4,5-trisphosphate 3-kinase A functions as a scaffold for synaptic Rac signaling. J. Neurosci. 29, 14039–14049 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Onouchi, Y. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature Genet. 40, 35–42 (2008). This intriguing study described a human ITPKC polymorphism that may associate with Kawasaki disease — the first genetic implication of an ITPK in a human disease. It also showed that ITPKC might negatively regulate Jurkat T cell activation.

    CAS  PubMed  Google Scholar 

  43. Muller, P., Kuttenkeuler, D., Gesellchen, V., Zeidler, M. P. & Boutros, M. Identification of JAK/STAT signalling components by genome-wide RNA interference. Nature 436, 871–875 (2005).

    PubMed  Google Scholar 

  44. Irvine, R. F. & Schell, M. J. Back in the water: the return of the inositol phosphates. Nature Rev. Mol. Cell Biol. 2, 327–338 (2001).

    CAS  Google Scholar 

  45. Irvine, R. Inositol phosphates: does IP4 run a protection racket? Curr. Biol. 11, R172–R174 (2001).

    CAS  PubMed  Google Scholar 

  46. Miller, A. T., Chamberlain, P. P. & Cooke, M. P. Beyond IP3: roles for higher order inositol phosphates in immune cell signaling. Cell Cycle 7, 463–467 (2008).

    CAS  PubMed  Google Scholar 

  47. Jia, Y., Schurmans, S. & Luo, H. R. Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate. Cell Cycle 7, 2803–2808 (2008).

    CAS  PubMed  Google Scholar 

  48. Cullen, P. J. et al. Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family. Nature 376, 527–530 (1995).

    CAS  PubMed  Google Scholar 

  49. Cozier, G. E. et al. GAP1IP4BP contains a novel group I pleckstrin homology domain that directs constitutive plasma membrane association. J. Biol. Chem. 275, 28261–28268 (2000).

    CAS  PubMed  Google Scholar 

  50. Bird, G. S. & Putney, J. W. Jr. Effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-activated Ca2+ signaling in mouse lacrimal acinar cells. J. Biol. Chem. 271, 6766–6770 (1996).

    CAS  PubMed  Google Scholar 

  51. Hermosura, M. C. et al. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature 408, 735–740 (2000).

    CAS  PubMed  Google Scholar 

  52. Klein, C. & Malviya, A. N. Mechanism of nuclear calcium signaling by inositol 1,4,5-trisphosphate produced in the nucleus, nuclear located protein kinase C and cyclic AMP-dependent protein kinase. Front. Biosci. 13, 1206–1226 (2008).

    CAS  PubMed  Google Scholar 

  53. Walker, S. A. et al. Analyzing the role of the putative inositol 1,3,4,5-tetrakisphosphate receptor GAP1IP4BP in intracellular Ca2+ homeostasis. J. Biol. Chem. 277, 48779–48785 (2002).

    CAS  PubMed  Google Scholar 

  54. Szinyei, C., Behnisch, T., Reiser, G. & Reymann, K. G. Inositol 1,3,4,5-tetrakisphosphate enhances long-term potentiation by regulating Ca2+ entry in rat hippocampus. J. Physiol. 516, 855–868 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Luckhoff, A. & Clapham, D. E. Inositol 1,3,4,5-tetrakisphosphate activates an endothelial Ca2+-permeable channel. Nature 355, 356–358 (1992).

    CAS  PubMed  Google Scholar 

  56. Tsubokawa, H., Oguro, K., Robinson, H. P., Masuzawa, T. & Kawai, N. Intracellular inositol 1,3,4,5-tetrakisphosphate enhances the calcium current in hippocampal CA1 neurones of the gerbil after ischaemia. J. Physiol. 497, 67–78 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hashii, M. et al. Bradykinin B2 receptor-induced and inositol tetrakisphosphate-evoked Ca2+ entry is sensitive to a protein tyrosine phosphorylation inhibitor in ras-transformed NIH/3T3 fibroblasts. Biochem. J. 319, 649–656 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Guse, A. H., Greiner, E., Emmrich, F. & Brand, K. Mass changes of inositol 1,3,4,5,6-pentakisphosphate and inositol hexakisphosphate during cell cycle progression in rat thymocytes. J. Biol. Chem. 268, 7129–7133 (1993).

    CAS  PubMed  Google Scholar 

  59. Guse, A. H., Roth, E., Broker, B. M. & Emmrich, F. Complex inositol polyphosphate response induced by co-cross-linking of CD4 and Fc γ receptors in the human monocytoid cell line U937. J. Immunol. 149, 2452–2458 (1992).

    CAS  PubMed  Google Scholar 

  60. Guse, A. H. & Emmrich, F. Determination of inositol polyphosphates from human T-lymphocyte cell lines by anion-exchange high-performance liquid chromatography and post-column derivatization. J. Chromatogr. 593, 157–163 (1992).

    CAS  PubMed  Google Scholar 

  61. Guse, A. H. & Emmrich, F. T-cell receptor-mediated metabolism of inositol polyphosphates in Jurkat T-lymphocytes. Identification of a D-myo-inositol 1,2,3,4,6-pentakisphosphate-2-phosphomonoesterase activity, a D-myo-inositol 1,3,4,5,6-pentakisphosphate-1/3-phosphatase activity and a D/L-myo-inositol 1,2,4,5,6-pentakisphosphate-1/3-kinase activity. J. Biol. Chem. 266, 24498–24502 (1991).

    CAS  PubMed  Google Scholar 

  62. Imboden, J. B. & Pattison, G. Regulation of inositol 1,4,5-trisphosphate kinase activity after stimulation of human T cell antigen receptor. J. Clin. Invest. 79, 1538–1541 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zilberman, Y., Howe, L. R., Moore, J. P., Hesketh, T. R. & Metcalfe, J. C. Calcium regulates inositol 1,3,4,5-tetrakisphosphate production in lysed thymocytes and in intact cells stimulated with concanavalin A. EMBO J. 6, 957–962 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Stewart, S. J., Kelley, L. L. & Powers, F. S. Production of inositol pentakisphosphate in a human T lymphocyte cell line. Biochem. Biophys. Res. Commun. 145, 895–902 (1987).

    CAS  PubMed  Google Scholar 

  65. Stewart, S. J. et al. Perturbation of the human T-cell antigen receptor-T3 complex leads to the production of inositol tetrakisphosphate: evidence for conversion from inositol trisphosphate. Proc. Natl Acad. Sci. USA 83, 6098–6102 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Imboden, J. B. & Stobo, J. D. Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores. J. Exp. Med. 161, 446–456 (1985). References 62, 63, 65 and 66 showed for the first time that lymphocyte antigen-receptor stimulation induces the accumulation of InsPs, including InsP 3 and InsP 4 , and Ca2+ release from intracellular stores.

    CAS  PubMed  Google Scholar 

  67. Ooms, L. M. et al. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem. J. 419, 29–49 (2009).

    CAS  PubMed  Google Scholar 

  68. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998).

    CAS  PubMed  Google Scholar 

  69. Caffrey, J. J., Darden, T., Wenk, M. R. & Shears, S. B. Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity. FEBS Lett. 499, 6–10 (2001).

    CAS  PubMed  Google Scholar 

  70. Pesesse, X. et al. The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate 5-phosphatase activity. FEBS Lett. 437, 301–303 (1998).

    CAS  PubMed  Google Scholar 

  71. Erneux, C., Govaerts, C., Communi, D. & Pesesse, X. The diversity and possible functions of the inositol polyphosphate 5-phosphatases. Biochim. Biophys. Acta 1436, 185–199 (1998).

    CAS  PubMed  Google Scholar 

  72. Astoul, E., Edmunds, C., Cantrell, D. A. & Ward, S. G. PI 3-K and T-cell activation: limitations of T-leukemic cell lines as signaling models. Trends Immunol. 22, 490–496 (2001).

    CAS  PubMed  Google Scholar 

  73. Resnick, A. C. et al. Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity. Proc. Natl Acad. Sci. USA 102, 12783–12788 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Alcazar-Roman, A. R. & Wente, S. R. Inositol polyphosphates: a new frontier for regulating gene expression. Chromosoma 117, 1–13 (2008).

    CAS  PubMed  Google Scholar 

  75. Leyman, A. et al. The absence of expression of the three isoenzymes of the inositol 1,4,5-trisphosphate 3-kinase does not prevent the formation of inositol pentakisphosphate and hexakisphosphate in mouse embryonic fibroblasts. Cell Signal. 19, 1497–1504 (2007).

    CAS  PubMed  Google Scholar 

  76. Shears, S. B. Molecular basis for the integration of inositol phosphate signaling pathways via human ITPK1. Adv. Enzyme Regul. 49, 87–96 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Frederick, J. P. et al. An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production. Proc. Natl Acad. Sci. USA 102, 8454–8459 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. von Boehmer, H. & Kisielow, P. Negative selection of the T-cell repertoire: where and when does it occur? Immunol. Rev. 209, 284–289 (2006).

    PubMed  Google Scholar 

  79. McGargill, M. A. et al. Cutting edge: extracellular signal-related kinase is not required for negative selection of developing T cells. J. Immunol. 183, 4838–4842 (2009).

    CAS  PubMed  Google Scholar 

  80. Neilson, J. R., Winslow, M. M., Hur, E. M. & Crabtree, G. R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004).

    CAS  PubMed  Google Scholar 

  81. Priatel, J. J., Teh, S. J., Dower, N. A., Stone, J. C. & Teh, H. S. RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. Immunity 17, 617–627 (2002).

    CAS  PubMed  Google Scholar 

  82. Dower, N. A. et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nature Immunol. 1, 317–321 (2000).

    CAS  Google Scholar 

  83. Qi, Q., Sahu, N. & August, A. Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors. J. Biol. Chem. 281, 38529–38534 (2006).

    CAS  PubMed  Google Scholar 

  84. Irvine, R. Cell signaling. The art of the soluble. Science 316, 845–846 (2007).

    CAS  PubMed  Google Scholar 

  85. Chamberlain, P. P. et al. Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B. Biochemistry 44, 14486–14493 (2005).

    CAS  PubMed  Google Scholar 

  86. Lucas, J. A., Felices, M., Evans, J. W. & Berg, L. J. Subtle defects in pre-TCR signaling in the absence of the Tec kinase Itk. J. Immunol. 179, 7561–7567 (2007).

    CAS  PubMed  Google Scholar 

  87. Felices, M., Yin, C. C., Kosaka, Y., Kang, J. & Berg, L. J. Tec kinase Itk in γδT cells is pivotal for controlling IgE production in vivo. Proc. Natl Acad. Sci. USA 106, 8308–8313 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Cozier, G., Sessions, R., Bottomley, J. R., Reynolds, J. S. & Cullen, P. J. Molecular modelling and site-directed mutagenesis of the inositol 1,3,4,5-tetrakisphosphate-binding pleckstrin homology domain from the Ras GTPase-activating protein GAP1IP4BP. Biochem. J. 349, 333–342 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Lockyer, P. J. et al. Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BPPH domain directing plasma membrane targeting. Curr. Biol. 7, 1007–1010 (1997).

    CAS  PubMed  Google Scholar 

  90. Windhorst, S. et al. Ins(1,4,5)P3 3-kinase-A overexpression induces cytoskeletal reorganization via a kinase-independent mechanism. Biochem. J. 414, 407–417 (2008).

    CAS  PubMed  Google Scholar 

  91. Windhorst, S. et al. Inositol 1, 4, 5-trisphosphate 3-kinase-A is a new cell motility-promoting protein that increases the metastatic potential of tumor cells by two functional activities. J. Biol. Chem. 285, 5541–5554 (2010).

    CAS  PubMed  Google Scholar 

  92. Culton, D. A. et al. Early preplasma cells define a tolerance checkpoint for autoreactive B cells. J. Immunol. 176, 790–802 (2006).

    CAS  PubMed  Google Scholar 

  93. Cambier, J. C., Gauld, S. B., Merrell, K. T. & Vilen, B. J. B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nature Rev. Immunol. 7, 633–643 (2007).

    CAS  Google Scholar 

  94. Cooke, M. P. et al. Immunoglobulin signal transduction guides the specificity of B cell–T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179, 425–438 (1994).

    CAS  PubMed  Google Scholar 

  95. Benschop, R. J., Brandl, E., Chan, A. C. & Cambier, J. C. Unique signaling properties of B cell antigen receptor in mature and immature B cells: implications for tolerance and activation. J. Immunol. 167, 4172–4179 (2001).

    CAS  PubMed  Google Scholar 

  96. Cozier, G. E., Carlton, J., Bouyoucef, D. & Cullen, P. J. Membrane targeting by pleckstrin homology domains. Curr. Top. Microbiol. Immunol. 282, 49–88 (2004).

    CAS  PubMed  Google Scholar 

  97. DiNitto, J. P. & Lambright, D. G. Membrane and juxtamembrane targeting by PH and PTB domains. Biochim. Biophys. Acta 1761, 850–867 (2006).

    CAS  PubMed  Google Scholar 

  98. Park, W. S. et al. Comprehensive identification of PIP3-regulated PH domains from C. elegans to H. sapiens by model prediction and live imaging. Mol. Cell 30, 381–392 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Dillon, S. B., Murray, J. J., Verghese, M. W. & Snyderman, R. Regulation of inositol phosphate metabolism in chemoattractant-stimulated human polymorphonuclear leukocytes. Definition of distinct dephosphorylation pathways for IP3 isomers. J. Biol. Chem. 262, 11546–11552 (1987).

    CAS  PubMed  Google Scholar 

  100. Feske, S. ORAI1 and STIM1 deficiency in human and mice: roles of store-operated Ca2+ entry in the immune system and beyond. Immunol. Rev. 231, 189–209 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Fukuda, M., Kojima, T., Kabayama, H. & Mikoshiba, K. Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. J. Biol. Chem. 271, 30303–30306 (1996).

    CAS  PubMed  Google Scholar 

  102. Rameh, L. E. et al. A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. J. Biol. Chem. 272, 22059–22066 (1997).

    CAS  PubMed  Google Scholar 

  103. Kojima, T., Fukuda, M., Watanabe, Y., Hamazato, F. & Mikoshiba, K. Characterization of the pleckstrin homology domain of Btk as an inositol polyphosphate and phosphoinositide binding domain. Biochem. Biophys. Res. Commun. 236, 333–339 (1997).

    CAS  PubMed  Google Scholar 

  104. Marone, R., Cmiljanovic, V., Giese, B. & Wymann, M. P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta 1784, 159–185 (2008).

    CAS  PubMed  Google Scholar 

  105. Hopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).

    CAS  Google Scholar 

  106. Gonzalez, B. et al. Structure of a human inositol 1,4,5-trisphosphate 3-kinase: substrate binding reveals why it is not a phosphoinositide 3-kinase. Mol. Cell 15, 689–701 (2004).

    CAS  PubMed  Google Scholar 

  107. Miller, G. J. & Hurley, J. H. Crystal structure of the catalytic core of inositol 1,4,5-trisphosphate 3-kinase. Mol. Cell. 15, 703–711 (2004).

    CAS  PubMed  Google Scholar 

  108. Holmes, W. & Jogl, G. Crystal structure of inositol phosphate multikinase 2 and implications for substrate specificity. J. Biol. Chem. 281, 38109–38116 (2006). References 85 and 106–108 described the crystal structures of ITPKA, ITPKB and IPMK.

    CAS  PubMed  Google Scholar 

  109. Chang, Y. T. et al. Purine-based inhibitors of inositol-1,4,5-trisphosphate-3-kinase. Chembiochem. 3, 897–901 (2002).

    CAS  PubMed  Google Scholar 

  110. Mayr, G. W., Windhorst, S. & Hillemeier, K. Antiproliferative plant and synthetic polyphenolics are specific inhibitors of vertebrate inositol-1,4,5-trisphosphate 3-kinases and inositol polyphosphate multikinase. J. Biol. Chem. 280, 13229–13240 (2005).

    CAS  PubMed  Google Scholar 

  111. Choi, G., Chang, Y.-T., Chung, S.-K. & Choi, K. Y. Molecular interactions of all possible regioisomers of synthetic myo-inositol phosphates with inositol 1,4,5-trisphosphate 3-kinase. Bioorg. Med. Chem. Lett. 7, 2709–2714 (1997).

    CAS  Google Scholar 

  112. Poinas, A. et al. Interaction of the catalytic domain of inositol 1,4,5-trisphosphate 3-kinase A with inositol phosphate analogues. Chembiochem. 6, 1449–1457 (2005).

    CAS  PubMed  Google Scholar 

  113. Liu, H. & Pope, R. M. Phagocytes: mechanisms of inflammation and tissue destruction. Rheum. Dis. Clin. North Am. 30, 19–39 (2004).

    PubMed  Google Scholar 

  114. Resnick, A. C. & Saiardi, A. Inositol polyphosphate multikinase: metabolic architect of nuclear inositides. Front. Biosci. 13, 856–866 (2008).

    CAS  PubMed  Google Scholar 

  115. Cunha-Melo, J. R., Dean, N. M., Moyer, J. D., Maeyama, K. & Beaven, M. A. The kinetics of phosphoinositide hydrolysis in rat basophilic leukemia (RBL-2H3) cells varies with the type of IgE receptor cross-linking agent used. J. Biol. Chem. 262, 11455–11463 (1987).

    CAS  PubMed  Google Scholar 

  116. Morrison, B. H., Bauer, J. A., Kalvakolanu, D. V. & Lindner, D. J. Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-β in ovarian carcinoma cells. J. Biol. Chem. 276, 24965–24970 (2001).

    CAS  PubMed  Google Scholar 

  117. Burton, A., Hu, X. & Saiardi, A. Are inositol pyrophosphates signalling molecules? J. Cell Physiol. 220, 8–15 (2009).

    CAS  PubMed  Google Scholar 

  118. Mulugu, S. et al. A conserved family of enzymes that phosphorylate inositol hexakisphosphate. Science 316, 106–109 (2007).

    CAS  PubMed  Google Scholar 

  119. Barker, C. J., Illies, C., Gaboardi, G. C. & Berggren, P. O. Inositol pyrophosphates: structure, enzymology and function. Cell. Mol. Life Sci. 66, 3851–3871 (2009).

    CAS  PubMed  Google Scholar 

  120. Lee, Y. S., Mulugu, S., York, J. D. & O'Shea, E. K. Regulation of a cyclin–CDK–CDK inhibitor complex by inositol pyrophosphates. Science 316, 109–112 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Stricker, R. et al. Interaction of the brain-specific protein p42IP4/centaurin-α with the peptidase nardilysin is regulated by the cognate ligands of p42IP4, PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4, with stereospecificity. J. Neurochem. 98, 343–354 (2006).

    CAS  PubMed  Google Scholar 

  122. Yang, S. N. et al. Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase. FASEB J. 15, 1753–1763 (2001).

    CAS  PubMed  Google Scholar 

  123. Larsson, O. et al. Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate. Science 278, 471–474 (1997).

    CAS  PubMed  Google Scholar 

  124. Mitchell, J. et al. An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC-3 function. Curr. Biol. 18, 1600–1605 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. York, J. D., Odom, A. R., Murphy, R., Ives, E. B. & Wente, S. R. A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285, 96–100 (1999).

    CAS  PubMed  Google Scholar 

  126. Alcazar-Roman, A. R., Tran, E. J., Guo, S. & Wente, S. R. Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nature Cell Biol. 8, 711–716 (2006).

    CAS  PubMed  Google Scholar 

  127. Bolger, T. A., Folkmann, A. W., Tran, E. J. & Wente, S. R. The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 134, 624–633 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Odom, A. R., Stahlberg, A., Wente, S. R. & York, J. D. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287, 2026–2029 (2000).

    CAS  PubMed  Google Scholar 

  129. Macbeth, M. R. et al. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309, 1534–1539 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Steger, D. J., Haswell, E. S., Miller, A. L., Wente, S. R. & O'Shea, E. K. Regulation of chromatin remodeling by inositol polyphosphates. Science 299, 114–116 (2003).

    CAS  PubMed  Google Scholar 

  131. Shen, X., Xiao, H., Ranallo, R., Wu, W. H. & Wu, C. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 299, 112–114 (2003).

    CAS  PubMed  Google Scholar 

  132. Luo, H. R. et al. Inositol pyrophosphates are required for DNA hyperrecombination in protein kinase c1 mutant yeast. Biochemistry 41, 2509–2515 (2002).

    CAS  PubMed  Google Scholar 

  133. Hanakahi, L. A., Bartlet-Jones, M., Chappell, C., Pappin, D. & West, S. C. Binding of inositol phosphate to DNA–PK and stimulation of double-strand break repair. Cell 102, 721–729 (2000).

    CAS  PubMed  Google Scholar 

  134. Saiardi, A., Resnick, A. C., Snowman, A. M., Wendland, B. & Snyder, S. H. Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. Proc. Natl Acad. Sci. USA 102, 1911–1914 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. York, S. J., Armbruster, B. N., Greenwell, P., Petes, T. D. & York, J. D. Inositol diphosphate signaling regulates telomere length. J. Biol. Chem. 280, 4264–4269 (2005).

    CAS  PubMed  Google Scholar 

  136. Saiardi, A., Bhandari, R., Resnick, A. C., Snowman, A. M. & Snyder, S. H. Phosphorylation of proteins by inositol pyrophosphates. Science 306, 2101–2105 (2004).

    CAS  PubMed  Google Scholar 

  137. York, J. D. & Hunter, T. Signal transduction. Unexpected mediators of protein phosphorylation. Science 306, 2053–2055 (2004).

    CAS  PubMed  Google Scholar 

  138. Lemmon, M. A. Pleckstrin homology domains: not just for phosphoinositides. Biochem. Soc. Trans. 32, 707–711 (2004).

    CAS  PubMed  Google Scholar 

  139. Medyouf, H. & Ghysdael, J. The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. Cell Cycle 7, 297–303 (2008).

    CAS  PubMed  Google Scholar 

  140. Huang, Y. H., Barouch-Bentov, R., Herman, A., Walker, J. & Sauer, K. Integrating traditional and postgenomic approaches to investigate lymphocyte development and function. Adv. Exp. Med. Biol. 584, 245–276 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Gascoigne, G. Mayr and Y. Hsing Huang for critical reading of the manuscript and valuable comments. We apologize to our colleagues for citing reviews instead of many important original references owing to space considerations. K.S. is supported by NIH grants AI070845 and GM088647.

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  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, 92037, California, USA

    Karsten Sauer & Michael P. Cooke

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Glossary

Inositol phosphate

(InsP). The consensus term for all phosphorylated D-myo-inositol derivatives. Mammalian cells produce many higher-order InsPs, including multiple phosphatidylinositol (PtdIns) or inositol (Ins) tris-, tetrakis- and pentakisphosphate isomers. To improve readability, we use the non-IUPAC acronyms PtdInsP3 for phosphatidylinositol-3,4,5-trisphosphate (standard abbreviation: PtdIns(3,4,5)P3), InsP3 for inositol-1,4,5-trisphosphate (standard abbreviation: Ins(1,4,5)P3) and InsP4 for inositol-1,3,4,5-tetrakisphosphate (standard abbreviation: Ins(1,3,4,5)P4) in this Review. This does not imply that PtdInsP3, InsP3 and InsP4 are the only, or the most important, InsPs.

Phosphoinositides

A family of phosphorylated derivatives of the membrane lipid phosphatidylinositol that contain a hydrophobic diacylglycerol backbone esterified to a polar inositol headgroup.

Second messenger

A signalling molecule such as InsP3 or DAG that is produced by a primary effector, usually an enzyme, that is in turn activated by a signal transducer downstream of a transmembrane receptor after its engagement by a first messenger ligand (for example, peptide–MHC complexes in the case of the T cell receptor). The second messenger can then activate one or more secondary effectors that further transmit signals into the cell.

Kawasaki disease

(Also known as mucocutaneous lymph node syndrome). An acute, self-limited vasculitis of infants and the leading cause of acquired heart disease among children in developed countries.

Store-operated Ca2+ entry

(SOCE). A mechanism used by many cells to increase intracellular Ca2+ concentrations and transduce signals in response to cell surface receptor ligation. This first results in the release of Ca2+ from intracellular stores. STIM proteins sense this depletion of Ca2+ stores and trigger the opening of plasma membrane Ca2+ channels containing ORAI proteins that mediate capacitative Ca2+ influx. In some cell types, other Ca2+ channels can contribute to SOCE.

Pleckstrin-homology (PH) domain

A structurally conserved protein domain of ∼ 120 amino acids that is found at least 305 times in the human genome. About 60 PH domains mediate protein membrane recruitment or protein–protein interactions by binding to phosphoinositides or to other proteins, respectively. The functions of most PH domains are unknown.

IL-2-inducible T cell kinase

(ITK). A T cell and NK cell expressed Tec family non-receptor protein tyrosine kinase that is involved in T cell receptor signalling.

Long-term potentiation

A long-lasting enhancement of synaptic transmission between two neurons thought to underlie learning and memory.

Feedback loop

A cause and effect circuit in which several processes occur in sequence and in which the output of a downstream process promotes or inhibits an upstream process, forming a circular signalling loop. Inhibitory loops (negative feedback) can increase the stability and accuracy of a signalling system by correcting unwanted changes. Activation loops (positive feedback) can amplify a signal by increasing the gain of the signal-transducing machinery.

Neonatal thymic organ culture

(NTOC). A method whereby neonatal thymic lobes are incubated in media in vitro. It allows monitoring of the effects of adding pharmacological agents on thymocyte development.

Feedforward loop

A cause and effect circuit in which several processes occur in sequence, and in which the output of an upstream process promotes or inhibits a downstream process, usually bypassing one or more intermediate processes. This can set the gain for a signalling circuit or specifically amplify or limit one of several different downstream signalling branches.

Innate-like CD8+ T cell

An αβ T cell subset characterized by high-level expression of CD44, CD122 and natural killer cell markers, indicative of an activated or memory phenotype. In contrast to conventional naive αβT cells, innate-like T cells are interleukin15 dependent and can exert effector functions immediately after stimulation. Whereas most conventional T cells are selected by peptide–MHC complexes on non-haematopoietic cells in the thymus, innate-like T cells are selected by MHC proteins on haematopoietic cells.

γδ T cell

A distinct lineage of T cells, the T cell receptor of which contains a γ and a δ chain instead of an α and a β chain. γδ T cells are not classical MHC restricted. Their antigenic ligands are largely unknown and might include non-peptides. γδ T cells have particularly important functions in epidermal tissues. They contribute to pathogen defence, tumour surveillance, mucosal and skin barrier functions and, in mice, skin wound healing.

RNA interference

(RNAi). An RNA-dependent gene silencing process initiated by short double-stranded RNA (dsRNA) molecules that can either be produced endogenously by the cell (micro RNA pathway) or be exogenously provided by viruses or through laboratory techniques. The cellular ribonuclease Dicer cleaves dsRNAs into 21–25 base pair small interfering RNAs (siRNAs) of which the 'guide strand' binds to complementary regions in cellular mRNAs within the RNA-induced silencing complex (RISC). This results in degradation of the mRNA and/or translational blockade.

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Sauer, K., Cooke, M. Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate. Nat Rev Immunol 10, 257–271 (2010). https://doi.org/10.1038/nri2745

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