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Signal Transduction—Associated and Cell Activation—Linked Antigens Expressed in Human Mast Cells


Mast cells (MCs) are multifunctional hematopoietic effector cells that produce and release an array of biologically active mediator substances. Growth and functions of MCs are regulated by cytokines, other extracellular factors, surface and cytoplasmic receptors, oncogene products, and a complex network of signal transduction cascades. Key regulators of differentiation of MCs appear to be stem cell factor (SCF) and its tyrosine kinase receptor KIT (c-kit proto-oncogene product=CD117), downstream-acting elements, and the mi transcription factor (MITF). Signaling through KIT is negatively regulated by the signal regulatory protein (SIRP)-α (CD172a)-SHP-1-pathway that is disrupted in neoplastic MCs in MC proliferative disorders. Both KIT and FcεRI are involved in MC activation and mediator release. Activation of MCs through FcεRI is associated with increased expression of activation-linked membrane antigens as well as with signaling events involving Lyn and Syk kinases, the phosphatidylinositol-3—kinase-pathway, Ras pathway, and the phospholipase C—protein kinase C pathway. A similar network of signaling is found in SCF-activated MCs. The current article gives an overview on signal transduction—associated and activation-linked antigens expressed in human MCs. Wherever possible the functional implication of signaling pathways and antigen expression are discussed.

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  1. 1.

    Valent P, Bettelheim P.Cell surface structures on human basophils and mast cells: biochemical and functional characterization.Adv Immunol. 1992;52:333–423.

  2. 2.

    Valent P, Schernthaner GH, Sperr WR, et al.Variable expression of activation-linked surface antigens on human mast cells in health and disease.Immunol Rev. 2001;179:74–81.

  3. 3.

    Galli SJ. Biology of disease: new insights into “the riddle of the mast cells”: microenvironmental regulation of mast cell development and phenotypic heterogeneity.Lab Invest. 1990;62:5–33.

  4. 4.

    Valent P. The riddle of the mast cell: c-kit ligand as missing link?Immunol Today. 1994;15:111–114.

  5. 5.

    Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell factor, and mast cells: what each is teaching us about the others.Am J Pathol. 1993;142:965–974.

  6. 6.

    Ishizaka T, Ishizaka K. Activation of mast cells for mediator release through IgE receptors.Prog Allergy. 1984;34:188–235.

  7. 7.

    Bischoff SC, Dahinden CA. c-kit ligand: a unique potentiator of mediator release by human lung mast cells.J Exp Med. 1992;175: 237–244.

  8. 8.

    Tsujimura T, Morii E, Nozaki M, et al. Involvement of transcription factor encoded by the mi locus in the expression of c-kit receptor tyrosine kinase in cultured mast cells of mice.Blood. 1996;88: 1225–1233.

  9. 9.

    Kitamura Y, Morii E, Jippo T, Ito A. mi-transcription factor as a regulator of mast cell differentiation.Int J Hematol. 2000;71: 197–202.

  10. 10.

    Wimazal F, Walchshofer S, Baghestanian M, et al. Detection ofmi transcription factor (MITF) mRNA in a case of myelodysplastic syndrome and bone marrow mastocytosis.Wien Klin Wochenschr. 1998;110:79–88.

  11. 11.

    Sillaber Ch, Bevec D, Ashman LK, et al. IL-4 regulates c-kit gene product expression in human myeloid-and mast cell progenitors.J Immunol. 1991;147:4224–4228.

  12. 12.

    Sillaber C, Sperr WR, Agis H, Spanblöchl E, Lechner K, Valent P. Inhibition of stem cell factor dependent formation of human mast cells by interleukin-3 and interleukin-4.Int Arch Allergy Immunol. 1994;105:264–268.

  13. 13.

    Yanagida M, Fukamachi H, Ohgami K, et al. Effects of T-helper 2- type cytokines, interleukin-3 (IL-3), IL-4, IL-5, and IL-6 on survival of cultured human mast cells.Blood. 1995;86:3705–3714.

  14. 14.

    Baghestanian M, Agis H, Bevec D, et al. Stem cell factor-induced downregulation of c-kit in human lung mast cells and HMC-1 mast cells.Exp Hematol. 1996;24:1377–1386.

  15. 15.

    Rottem M, Okada T, Goff JP, Metcalfe DD. Mast cells cultured from peripheral blood of normal donors and patients with masto- cytosis originate from a CD34+/FceRI cell population.Blood. 1994;84:2489–2496.

  16. 16.

    Xia HZ, Du Z, Craig S, et al. Effect of recombinant human IL-4 on tryptase, chymase, and Fc epsilon receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells.J Immunol. 1997;159:2911–2921.

  17. 17.

    Toru H, Ra C, Nonoyama S, Suzuki K, Yata J, Nakahata T. Induction of the high affinity IgE receptor (Fc epsilon RI) on human mast cells by IL-4.Int Immunol. 1996;8:1367–1373.

  18. 18.

    Furuichi K, Rivera J, Isersky C. The receptor for immunoglobulin E on rat basophilic leukemia cells: effects of ligand binding on receptor expression.Proc Natl Acad Sci U S A. 1985;82:1522–1525.

  19. 19.

    Yamaguchi M, Lantz CS, Oettgen HC, et al. IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions.J Exp Med. 1997;185:663–672.

  20. 20.

    Malveaux FJ, Conroy MC, Adkinson NF, Lichtenstein LM. IgE receptors on human basophils: relationship to serum IgE concentrations.J Clin Invest. 1978;62:176–181.

  21. 21.

    Sattler M, Salgia R, Shrikhande G, et al. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL).J Biol Chem. 1997;272:10248–10253.

  22. 22.

    Tauchi T, Feng GS, Marshall MS, et al. The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells.J Biol Chem. 1994;269:25206–25211.

  23. 23.

    Blume-Jensen P, Ronnstrand L, Gout I, Waterfield MD, Heldin CH. Modulation of Kit/stem cell factor receptor-induced signaling by protein kinase C.J Biol Chem. 1994;269:21793–21802.

  24. 24.

    Taylor ML, Metcalfe DD. Kit signal transduction.Hematol Oncol North Am. 2000;14:517–535.

  25. 25.

    Boissan M, Feger F, Guillosson JJ, Arock M. c-Kit and c-kit mutations in mastocytosis and other hematologic disorders.J Leukoc Biol. 2000;67:135–148.

  26. 26.

    O’Laughlin-Bunner B, Radosevic N, Taylor ML, et al. Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells.Blood. 2001;98:343–350.

  27. 27.

    Ishizuka T, Chayama K, Takeda K, et al. Mitogen-activated protein kinase activation through Fce receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells.J Immunol. 1999;162:2087–2094.

  28. 28.

    Huber M, Helgason CD, Scheid MP, Duronio V, Humphries RK, Krystal G. Targeted disruption of SHIP leads to Steel factor- induced degranulation of mast cells.EMBO J. 1998;17:7311–7319.

  29. 29.

    De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R. Socs-1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation.EMBO J. 1999;18: 904–915.

  30. 30.

    Kharitoenkov A, Chen Z, Sures I, Wang H, Schilling J, Ullrich A. A family of receptors that inhibit signalling through tyrosine kinase receptors.Nature. 1997;386:181–186.

  31. 31.

    Lienard H, Bruhns P, Malbec O, Fridman WH, Daeron M. Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation.J Biol Chem. 1999;274:32493–32499.

  32. 32.

    Ghannadan M, Hauswirth A, Schernthaner G-H, et al. Detection of novel CD antigens on the surface of human mast cells and basophils. Int Arch Allergy Immunol. In press.

  33. 33.

    Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Simonovitch KA. SHP-1 binds to and negatively modulates the c-kit receptor by interacting with Tyrosine 569 in the c-Kit juxtamembrane domain.Mol Cell Biol. 1998;18:2089–2099.

  34. 34.

    Piao X, Paulson R, van der Geer P, Pawson T, Bernstein A. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1.Proc Natl Acad Sci U S A. 1996;93:14665–14669.

  35. 35.

    Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogenec-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder.Proc Natl Acad Sci U S A. 1995;92:10560–10564.

  36. 36.

    Longley BJ, Tyrrell L, Lu SZ, et al. Somatic c-kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm.Nat Genet. 1996; 12:312–314.

  37. 37.

    Longley BJ, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis.Proc Natl Acad Sci U S A. 1999;96:1609–1614.

  38. 38.

    Huber M, Helgason CD, Damen JE, Liu L, Humphries RK, Krystal G. The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation.Proc Natl Acad Sci U S A. 1998;95:11330–11335.

  39. 39.

    Kinet JP. The high affinity IgE receptor (FcεRI): from physiology to pathology.Ann Rev Immunol. 1999;17:931–972.

  40. 40.

    Ishizaka T, Conrad DH, Schulman ES, Sterk AR, Ishizaka K. Biochemical analysis of initial triggering events of IgE-mediated histamine release from human lung mast cells.J Immunol. 1983;130: 2357–2362.

  41. 41.

    Ishizaka T, Foreman JC, Sterk AR, Ishizaka K. Induction of calcium flux across the rat mast cell membrane by bridging IgE receptors.Proc Natl Acad Sci U S A. 1979;76:5858–5862.

  42. 42.

    Dvorak AM, Massey W, Warner J, Kissell S, Kagey-Sobotka A, Lichtenstein LM. IgE-mediated anaphylactic degranulation of isolated human skin mast cells.Blood. 1991;77:569–578.

  43. 43.

    Bühring HJ, Seiffert M, Giesert C, et al. The basophil activation marker defined by antibody 97A6 is identical with the ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3).Blood. 2001; 97:3303–3306.

  44. 44.

    Bühring HJ, Simmons PJ, Pudney M, et al. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors.Blood. 1999;94:2343–2356.

  45. 45.

    Fleming TJ, Donnadieu E,Song CH,Van Laethem F, Galli SJ, Kinet JP. Negative regulation of FceRI-mediated degranulation by CD81.J Exp Med. 1997;186:1307–1314.

  46. 46.

    Ghannadan M, Baghestanian M,Wimazal F, et al. Phenotypic characterization of human skin mast cells by combined staining for toluidine blue and CD antibodies.J Invest Dermatol. 1998;111: 689–695.

  47. 47.

    Eiseman E, Bolen JB. Engagement of the high affinity IgE receptor activates src protein-related tyrosine kinases.Nature. 1992;355: 78–80.

  48. 48.

    White HR, Pluznik DH, Ishizaka K, Ishizaka T. Antigen-induced increase in protein kinase C activity in plasma membrane of mast cells.Proc Natl Acad Sci U S A. 1985;82:8193–8197.

  49. 49.

    Benhamou M, Ryba NJ, Kihara H, Nishikata H, Siraganian RP. Protein-tyrosine kinase p72syk in high affinity IgE receptor signaling: identification as component of pp72 and association with the receptor gamma chain after receptor aggregation.J Biol Chem. 1993;268:23318–23324.

  50. 50.

    Kihara H, Siraganian RP. Src homology 2 domains Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor.J Biol Chem. 1994;269:22427–22432.

  51. 51.

    Barker SA, Lujan D, Wilson BS. Multiple roles in PI 3-kinase in the regulation of PLCgamma activity and Ca2+ mobilization in antigen-stimulated mast cells.J Lekoc Biol. 1999;65:321–329.

  52. 52.

    Beaven MA, Metzger H. Signal transduction of by Fc receptors: the Fc epsilon RI case.Immunol Today. 1993;14:222–226.

  53. 53.

    Nadler MJ, Matthews SA, Turner H, Kinet JP. Signal transduction by the high-affinity immunoglobulin E receptor Fc epsilon RI.Adv Immunol. 2000;76:325–355.

  54. 54.

    Graham TE, Pfeiffer JR, Lee RJ, et al. MEK and ERK activation in ras-disabled RBL-2H3 mast cells and novel roles for geranyl- geranylated and farnesylated proteins in Fc epsilonRI-mediated signaling.J Immunol. 1998;161:6733–6744.

  55. 55.

    Jouvin MH, Adamczewski M, Numerof R, Letourneur O, Valle A, Kinet JP. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor.J Biol Chem. 1994;269:5918–5925.

  56. 56.

    Zhang J, Siraganian RP. CD45 is essential for FcεRI signaling by ZAP70, but not Syk, in Syk-negative mast cells.J Immunol. 1999; 63:2508–2516.

  57. 57.

    Zhang J, Berenstein EH, Evans RL, Siraganian RP. Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells.J Exp Med. 1996;184:71–79.

  58. 58.

    Kepley CL, Youssef L, Andrews RP, Wilson BS, Oliver JM. Multiple defects in Fc epsilon RI signaling in Syk-deficient nonreleaser basophils and IL-3-induced recovery of Syk expression and secretion.J Immunol. 2000;165:5913–5920.

  59. 59.

    Kimura T, Sakamoto H,Appella E, Siraganian RP. The negative signaling molecule SH2 domain-containing inositol-polyphosphate 5- phosphatase (SHIP) binds to the tyrosine-phosphorylated β subunit of the high affinity IgE receptor.J Biol Chem. 1997;272:13991–13996.

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Correspondence to Peter Valent or Minoo Ghannadan or Alexander W. Hauswirth or Gerit-Holger Schernthaner or Wolfgang R. Sperr or Michel Arock.

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Valent, P., Ghannadan, M., Hauswirth, A.W. et al. Signal Transduction—Associated and Cell Activation—Linked Antigens Expressed in Human Mast Cells. Int J Hematol 75, 357–362 (2002).

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Key words

  • KIT
  • SCF
  • FceRI
  • SHP-1
  • SIRP-α
  • CD203c