Signaling in Mast Cells

  • Anthony P. Sampson
  • Martin K. Church


Mast cells release preformed granule-associated mediators (histamine, tryptase, and cytokines) and de novo-synthesized mediators (eicosanoids) when antigen crosslinks immunoglobulin E (IgE) bound to its high-affinity receptor (FcεRI) . These mediators play central roles in the immediate reactions to allergen exposure in rhinitis and asthma and may also initiate and perpetuate chronic inflammation. The biochemical mechanisms that transduce and amplify the antigen-binding signal into a cellular response are not fully understood even in animal cell lines (1) and are complicated by crosstalk between different signaling pathways. This complexity may arise from the need for a mast cell to remain quiescent when IgE binds to its high-affinity receptor but to release mediators explosively when IgE receptors are crosslinked by multivalent antigen. Understanding this unique complexity may help in the development of novel pharmacological agents for antiallergy therapy. This chapter will outline the emerging consensus on the most prominent signal transduction pathways in mast cells.


Mast Cell Histamine Release Human Mast Cell Tumor Mast Cell Human Lung Mast Cell 
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  1. 1.
    Razin E, Pecht I, Rivera J (1995) Signal transduction in the activation of mast cells and basophils. Immunol Today 16: 370–373.PubMedCrossRefGoogle Scholar
  2. 2.
    Siraganian RP, Hook WA, Levine BB (1975) Specific in vitro histamine release from basophils by bivalent haptens: evidence of activation by simple bridging of membrane bound antibody. Immunochemistry 12: 149–156.CrossRefGoogle Scholar
  3. 3.
    Segal DM, Taurog JD, Metzger H (1977) Dimeric immunoglobulin E serves as a unit signal for mast cell degranulation. Proc Natl Acad Sci USA 74: 2993–2997.CrossRefGoogle Scholar
  4. 4.
    Robertson D, Holowka D, Baird B (1986) Cross-linking of immunoglobulin E-receptor complexes induces their interaction with the cytoskeleton of rat basophilic leukemia cells. J Immunol 136: 4565–4572.PubMedGoogle Scholar
  5. 5.
    Caulfield JP, El Lati S, Thomas G, Church MK (1990) Dissociated human foreskin mast cells degranulate in response to anti-IgE and substance P. Lab Invest 63: 502–510.PubMedGoogle Scholar
  6. 6.
    Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–205.PubMedCrossRefGoogle Scholar
  7. 7.
    Schrader JW, Welham MJ, Leslie KB, Duronio V (1995) Cytokine-mediated signal transduction in mast cells. In: Kitamura Y, Yamamura S, Galli SJ, Greaves MW, eds. Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function. Raven, New York, pp. 65–77.Google Scholar
  8. 8.
    Bertics PJ, Gill GN (1985) Self-autophosphorylation enhances the protein tyrosine kinase activity of the epidermal growth factor receptor. J Biol Chem 260:14, 642–14, 647.Google Scholar
  9. 9.
    Koch CA, Anderson D, Moran MF, Ellis C, Pawson T (1991) SH2 and SH3 domains elements that control interactions of cytoplasmic signalling proteins. Science 252: 668–674.PubMedCrossRefGoogle Scholar
  10. 10.
    Benhamou M, Gutking JS, Robbins KC, Siraganian RP (1990) Tyrosine phosphorylation coupled to IgE receptor mediated signal transduction and histamine release. Proc Natl Acad Sci USA 87: 5327–5332.PubMedCrossRefGoogle Scholar
  11. 11.
    Gauen LK, Zhu Y, Letourneur F, Hu Q, Bolen JB, Matis LA, Klausner RD, Shaw A (1994) Interactions of p59 fynand Zap-70 with T-cell receptor activation motifs: defining the nature of a signalling motif. Mol Cell Biol 14: 3729–3741.PubMedGoogle Scholar
  12. 12.
    Eiseman E, Bolen JB (1992) Engagement of the high affinity IgE receptor activates src protein related tyrosine kinases. Nature 355: 78–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Jouvin MH, Adamczewski M, Numerof R, Letourneur O, Valle A, Kinet JP (1994) Differential control of the tyrosine kinases lyn and syk by the two signalling chains of the high affinity immunoglobulin E receptor. J Biol Chem 269: 5918–5925.Google Scholar
  14. 14.
    Penhallow RC, Class K, Sonoda H, Bolen JB, Rowley RB (1995) Temporal activation of nontransmembrane protein tyrosine kinases following mast cell FcERI engagement. J Biol Chem 270:23, 362–23, 365.Google Scholar
  15. 15.
    Oliver JM, Burg DL, Deanin GG, Mclaughlin JL, Geahlen RL (1994) Role of the protein tyrosine kinase, syk, in signal transduction in mast cells: inhibition of FcERI-mediated signalling by the syk-selective inhibitor, piceatannol. J Biol Chem 269:29, 697–29, 703.Google Scholar
  16. 16.
    Wilson BS, Kapp N, Lee RJ, Pfeiffer JR, Martinez AM, Platt Y, Letourneur F, Oliver JM (1995) Distinct functions of the FceRI y and 13 subunits in the control of FceRI-mediated tyrosine kinase activation and signalling responses in RBL-2H3 mast cells. J Biol Chem 270: 4013–4022.Google Scholar
  17. 17.
    Paolini R, Jouvin MH, Kinet JP (1991) Phosphorylation and dephosphorylation of the high-affinity receptor for immunoglobulin E immediately after receptor engagement and disengagement. Nature 353: 855–858.Google Scholar
  18. 18.
    Kinet JP (1992) The gamma-zeta dimers of Fc receptors as connectors to signal transduction. Curr Opin Immunol 4: 43–48.Google Scholar
  19. 19.
    Hutchcroft JE, Geahlen RL, Deanin GG, Oliver JM (1992) FceRI-mediated tyrosine phosphorylation and activation of the 72kDa protein tyrosine kinase, PTK72, in RBL-2H3 rat tumor mast cells. Proc Natl Acad Sci USA 89: 9107–9111.Google Scholar
  20. 20.
    Minoguchi K, Benhamou M, Swaim WD, Kawakami Y, Kawakami T, Siraganian RP (1994) Activation of the protein tyrosine kinase p72sY by FceRI aggregation in rat basophilic leukemia cells. J Biol Chem 269:16, 902–16, 908.Google Scholar
  21. 21.
    Lavens SE, Peachell PT, Warner JA (1992) Role of tyrosine kinases in IgE-mediated signal transduction in human lung mast cells and basophils. Am J Respir Cell Mol Biol 7: 637–644.PubMedGoogle Scholar
  22. 22.
    Stephan V, Benhamou M, Gutkind JS, Robbins KC, Siraganian RP (1992) FcsRI-induced protein-tyrosine phosphorylation of pp72 in rat basophilic leukemia cells RBL-2H3: evidence for a novel signal transduction pathway unrelated to G protein activation and phophatydylinositol hydrolysis. J Biol Chem 267: 5434–5441.Google Scholar
  23. 23.
    Kawakami T, Kawakami Y, Yao L, Fukamachi H, Matsuoka S, Miura T (1995) Tyrosine kinases and their substrates in the FceRI signaling pathway. In: Kitamura Y, Yamamura S, Galli SJ, Greaves MW, eds. Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function. Raven, New York, pp. 249–261.Google Scholar
  24. 24.
    Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR (1990) Interaction of the unique N-terminal region of tyrosine kinase p5 ’ with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60: 755–765.Google Scholar
  25. 25.
    Hook WA, Berenstein EH, Zinsser FU, Fischler C, Siraganian RP (1991) Monoclonal antibodies to the leukocyte common antigen (CD45) inhibit IgE-mediated histamine release from human basophils. J Immunol 147: 2670–2676.PubMedGoogle Scholar
  26. 26.
    Peachell PT, Munday MR (1993) Regulation of human lung mast cell function by phosphatase inhibitors. J Immunol 151: 3808–3816.PubMedGoogle Scholar
  27. 27.
    Kennerly DA (1990) Phosphatidylcholine is a quantitatively more important source of increased 1, 2-diacylglycerol than is phosphatidylinositol in mast cells. J Immunol 144: 3912–3919.PubMedGoogle Scholar
  28. 28.
    Rhee SG, Suh PG, Ryu SH, Lee SY (1989) Studies of inositol phospholipid-specific phospholipase C. Science 244: 546–550.PubMedCrossRefGoogle Scholar
  29. 29.
    Nishibe S, Wahl MI, Hernandez-Sotomayor SM, Tonks NK, Rhee SG, Carpenter G (1990) Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation. Science 250: 1253–1256.PubMedCrossRefGoogle Scholar
  30. 30.
    Stryer L, Boume HR (1986) G proteins: a family of signal transducers. Annu Rev Cell Biol 2: 391–419.PubMedCrossRefGoogle Scholar
  31. 31.
    Bar-Sagi D, Gomperts BD (1988) Stimulation of exocytotic degranulation by microinjection of the ras oncogene protein in rat mast cells. Oncogene 3: 463–468.PubMedGoogle Scholar
  32. 32.
    Cunha-Melo JR, Gonzago HM, Ali H, Huang FL, Huang KP, Beaven MA (1989) Studies of protein kinase C in the rat basophilic leukemia RBL-2H3 cell reveal that antigen-induced signals are not mimicked by the actions of phorbol myristate acetate and Ca ionophore. J Immunol 143: 2617–2625.PubMedGoogle Scholar
  33. 33.
    Ali H, Collado-Escobar DM, Beaven MA (1989) The rise in concentration of free Calf and of pH provides sequential, synergistic signals for secretion in antigen-stimulated rat basophilic leukemia RBL-2H3 cells. J Immunol 143: 2626–2633.PubMedGoogle Scholar
  34. 34.
    Von zur Mühlen F, Eckstein F, Penner R (1991) Guanosine 5’-[beta-thioltriphosphate selectively activates calcium signalling in mast cells. Proc Natl Acad Sci USA 88: 926–930.Google Scholar
  35. 35.
    Nakamura T, Ui M (1983) Suppression of passive cutaneous anaphylaxis by pertussis toxin, an islet-activating protein, as a result of inhibition of histamine release by mast cells. Biochem Pharmacol 32: 3435–3441.PubMedCrossRefGoogle Scholar
  36. 36.
    Saito H, Okajima F, Molski TF, Sha’afi RI, Ui M, Ishizaka T (1988) Effect of cholera toxin on histamine release from bone marrow-derived mouse mast cells. Proc Natl Acad Sci USA 85: 2504–2508.PubMedCrossRefGoogle Scholar
  37. 37.
    Bennett JP, Cockcroft S, Gomperts BD (1981) Rat mast cells permeabilized with ATP secrete histamine in response to calcium ions buffered in the micromolar range. J Physiol) Lond) 317: 335–345.Google Scholar
  38. 38.
    Theoharides TC, Douglas WW (1978) Secretion in mast cells induced by calcium entrapped within phospholipid vesicles. Science 201: 1143–1145.PubMedCrossRefGoogle Scholar
  39. 39.
    Takaishi T, Siraganian RP (1985) Changes in 45Ca2 flux following the activation of rat basophilic leukemia cells for histamine release. Ann Allergy 55:353 abstract.Google Scholar
  40. 40.
    Stump RF, Oliver JM, Cragoe EJ, Deanin GG (1987) The control of mediator release from RBL-2H3 cells: roles for Cat, Na’, and protein kinase Cl. J Immunol 139: 881–886.Google Scholar
  41. 41.
    Mohr FC, Fewtrell C (1987) The relative contributions of extracellular and intracellular calcium to secretion from tumor mast cells: multiple effects of the proton ionophore carbonyl cyanide m-chlorophenylhydrazone. J Biol Chem 262:10, 638–10, 643.Google Scholar
  42. 42.
    Matthews G, Neher E, Penner R (1989) Second messenger-activated calcium influx in rat peritoneal mast cells. J Physiol (Lond) 418: 105–130.Google Scholar
  43. 43.
    Penner R, Matthews G, Neher E (1988) Regulation of calcium influx by second messengers in rat mast cells. Nature 334: 499–501.PubMedCrossRefGoogle Scholar
  44. 44.
    MacGlashan DW (1989) Single cell analysis of Cat changes in human lung mast cells: graded vs. allor-nothing elevations after IgE-mediated stimulation. J Cell Biol 109: 123–134.PubMedCrossRefGoogle Scholar
  45. 45.
    White JR, Pluznik DH, Ishizaka K, Ishizaka T (1985) Antigen-induced increase in protein kinase C activity in plasma membrane of mast cells. Proc Natl Acad Sci USA 82: 8193–8197.PubMedCrossRefGoogle Scholar
  46. 46.
    Sagi-Eisenberg R, Pecht I (1984) Protein kinase C, a coupling element between stimulus and secretion of basophils. Immunol Lett 8: 237–241.PubMedCrossRefGoogle Scholar
  47. 47.
    Sagi-Eisenberg R, Lieman H, Pecht I (1985) Protein kinase C regulation of the receptor-coupled calcium signal in histamine-secreting rat basophilic leukaemia cells. Nature 313: 59–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Howell TW, Kramer IM, Gomperts BD (1989) Protein phosphorylation and the dependence on Cat+ and GTP-y-S for exocytosis from permeabilised mast cells. Cell Signal 1: 157–163.PubMedCrossRefGoogle Scholar
  49. 49.
    Koopmann WR, Jackson RC (1990) Calcium-and guanine-nucleotide-dependent exocytosis in permeabilized mast cells: modulation by protein kinase C. Biochem J 265: 365–373.PubMedGoogle Scholar
  50. 50.
    Okayama Y, Semper A, Holgate ST, Church MK (1995) Multiple cytokine mRNA expression in human mast cells stimulated via FceRI. Int Arch Allergy Immunol 107: 158–159.Google Scholar
  51. 51.
    Lin L-L, Lin AY, Knopf JL (1992) Cytosolic phospholipase A2 is coupled to hormonally-regulated release of arachidonic acid. Proc Natl Acad Sci USA 89: 6147–6151.Google Scholar
  52. 52.
    Lin L-L, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72: 269–278.Google Scholar
  53. 53.
    Snyder F (1985) Chemical and biochemical aspects of platelet activating factor: a novel class of acetylated ether-linked choline phospholipids. Med Res Rev 5: 107–140.PubMedCrossRefGoogle Scholar
  54. 54.
    Narasimhan V, Holowka D, Baird B (1990) A guanine nucleotide binding protein participates in IgE receptor-mediated activation of endogenous and reconstituted phopholipase A2 in a permeabilized cell system. J Biol Chem 265: 1459–1464.PubMedGoogle Scholar
  55. 55.
    Murakami M, Austen KF, Aim JP (1995) Cytokine regulation of arachidonic acid metabolism in mast cells. In: Kitamura Y, Yamamura S, Galli SJ, Greaves MW eds. Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function. Raven, New York, pp. 25–37.Google Scholar
  56. 56.
    Ali A, Ford-Hutchinson AW, Nicholson DW (1994) Activation of protein kinase C down-regulates leukotriene C4 synthase activity and attenuates cysteinyl leukotriene production in an eosinophilic sub-strain of HL-60 cells. J Immunol 153: 776–788.Google Scholar
  57. 57.
    MacGlashan DW, Schleimer RP, Peters SP, Schulman ES, Adams GK, Kagey-Sobotka A, Newball HH, Lichtenstein LM (1983) Comparative studies of human basophils and mast cells. Fed Proc 42: 2504–2509.PubMedGoogle Scholar
  58. 58.
    Peachell PT, MacGlashan DW, Lichtenstein LM, Schleimer RP (1988) Regulation of human basophil and lung mast cell function by cyclic adenosine monophosphate. J Immunol 140: 571–579.PubMedGoogle Scholar
  59. 59.
    Morita Y, Siraganian RP (1981) Inhibition of IgE-mediated histamine release from rat basophilic leukemia cells and rat mast cells by inhibitors of transmethylation. J Immunol 127: 1339–1344.PubMedGoogle Scholar

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© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Anthony P. Sampson
  • Martin K. Church

There are no affiliations available

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