Review and feature article
Molecular regulation of mast cell activation

https://doi.org/10.1016/j.jaci.2006.04.015Get rights and content

The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (FcɛRI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses.

Section snippets

FcɛRI structure and function: ITAMs as positive and negative regulatory motifs

The FcɛRI expressed on mast cells and basophils is a tetrameric receptor4 comprised of the IgE-binding α chain, the membrane-tetraspanning β chain, and a disulfide-linked homodimer of the γ chains (Fig 1). The β chain functions as an amplifying module20 for this receptor, and in its absence the receptor initiates weak signals. The γ chain homodimer imparts signaling competence to this receptor.4 Both the β and γ chains contain the ITAM motifs demonstrated to be essential for the amplifying and

Regulation by receptor-proximal tyrosine kinases

FcɛRI-mediated activation of mast cells requires both Lyn and the related Src PTK Fyn (Fig 2) as receptor-proximal kinases.32 As discussed above, Lyn is essential for the phosphorylation of FcɛRIβ and FcɛRIγ ITAMs, but because residual FcɛRI phosphorylation was observed in Lyn-null mast cells,33, 34, 35 other kinases are likely required or can substitute. In addition to Lyn, Fyn was found to be activated by FcɛRI engagement, and this initiates signals that complement Lyn-mediated responses

Regulatory function of molecular adaptors

As alluded to above, activation of mast cells requires the formation of a multimolecular signaling complex conceptually termed signalosome, which contains the necessary machinery to regulate downstream cellular processes. These signaling complexes (Fig 2) must be localized to specific regions within the plasma membrane that allow interactions with proteins or novel lipids generated by aggregation of surface receptors.48 Such events are coordinated by specific proteins termed adaptor (also

PI3K, a central player in mast cell activation and function

By catalyzing the production of phosphatidylinositol 3, 4, 5-trisphosphate (PIP3), PI3K plays a critical role in mast cell degranulation and cytokine production.32, 46, 64, 65, 66 A large number of key signaling molecules contain a pleckstrin homology (PH) domain that binds PIP3 and serves to target these molecules to membranes and enhance their activity. Some key regulatory molecules, such as protein kinase C (PKC), PLCγ, PI3K-dependent protein kinase 1 (PDK1), Btk, phospholipase D (PLD), and

Phospholipases in mast cell function

Molecules derived from the hydrolysis of phospholipids provide both substrates for the production of eicosanoids and secondary signaling molecules for the regulation of the pathways that lead to the release of these and other classes of inflammatory mediators from activated mast cells. These reactions are catalyzed by phospholipase (PL) A2, PLC, and PLD, which are activated after aggregation of FcɛRI and ligation of other receptors, such as Kit, expressed on the mast cell surface.

Closing remarks

Evident from the remarks herein, our increase in the knowledge of the events regulating mast cell activation has revealed an increasing complexity that underlies the presumed simplicity of a mast cell's response to a stimulus. Several lessons can be learned. First, for a given response, such as degranulation, many molecules function in a coordinated manner to promote and control the rate and extent of this response (Fig 2). Molecular redundancy is evident because only a few molecules seemingly

References (119)

  • B. Pasquier et al.

    Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM

    Immunity

    (2005)
  • M.L. Hibbs et al.

    Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease

    Cell

    (1995)
  • H. Kihara et al.

    Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor

    J Biol Chem

    (1994)
  • M.-H.E. Jouvin et al.

    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)
  • M. Deckert et al.

    Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases

    J Biol Chem

    (1998)
  • J. Rivera

    Molecular adapters in FcɛRI signaling and the allergic response

    Curr Opin Immunol

    (2002)
  • C. Tkaczyk et al.

    NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following KIT activation and FcɛRI aggregation

    Blood

    (2004)
  • S. Saitoh et al.

    LAT is essential for FcɛRI-mediated mast cell activation

    Immunity

    (2000)
  • Y. Fujii et al.

    Targeting of MIST to Src-family kinases via SKAP55-SLAP-130 adaptor complex in mast cells

    FEBS Lett

    (2003)
  • A.J. Smith et al.

    p110β and p110δ phosphatidylinositol 3-kinase up-regulate FcɛRI-activated Ca2+ influx by enhancing inositol 1, 4, 5-trisphosphate production

    J Biol Chem

    (2001)
  • D.A. Windmiller et al.

    Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein coupled versus FcɛRI receptors

    J Biol Chem

    (2003)
  • J.M. Lu-Kuo et al.

    Impaired Kit- but not FcɛRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85α gene products

    J Biol Chem

    (2000)
  • C.P. Baran et al.

    The inositol 5′-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity

    J Biol Chem

    (2003)
  • S.G. Rhee et al.

    Regulation of inositol phospholipid-specific phospholipase C isozymes

    J Biol Chem

    (1992)
  • S. Iwaki et al.

    Btk plays a crucial role in the amplification of FcɛRI-mediated mast cell activation by Kit

    J Biol Chem

    (2005)
  • C. Tkaczyk et al.

    The phospholipase Cγ1-dependent pathway of FcɛRI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase

    J Biol Chem

    (2003)
  • K. Ozawa et al.

    Ca2+-dependent and Ca2+-independent isozymes of protein kinase C mediate exocytosis in antigen-stimulated rat basophilic RBL-2H3 cells

    J Biol Chem

    (1993)
  • H. Nechushtan et al.

    Inhibition of degranulation and interleukin-6 production in mast cells derived from mice deficient in protein kinase Cβ

    Blood

    (2000)
  • P. Germano et al.

    Phosphorylation of the γ chain of the high affinity receptor for immunoglobulin E by receptor-associated protein kinase C-δ

    J Biol Chem

    (1994)
  • K. Ozawa et al.

    Different isozymes of protein kinase C mediate feedback inhibition of phospholipase C and stimulatory signals for exocytosis in rat RBL-2H3 cells

    J Biol Chem

    (1993)
  • R.I. Ludowyke et al.

    Antigen-induced secretion of histamine and the phosphorylation of myosin by protein kinase C in rat basophilic leukemia cells

    J Biol Chem

    (1989)
  • Y. Shimazaki et al.

    Phosphorylation of 25-kDa synaptosome-associated protein. Possible involvement in protein kinase C-mediated regulation of neurotransmitter release

    J Biol Chem

    (1996)
  • S.H. Chung et al.

    Protein kinase C phosphorylation of syntaxin 4 in thrombin-activated human platelets

    J Biol Chem

    (2000)
  • J. Polgar et al.

    Phosphorylation of SNAP-23 in activated human platelets

    J Biol Chem

    (2003)
  • A. Chahdi et al.

    Serine/threonine protein kinases synergistically regulate phospholipase D1 and 2 and secretion in RBL-2H3 mast cells

    Mol Immunol

    (2002)
  • S.J. Galli et al.

    Mast cells as “tunable” effector and immunoregulatory cells: recent advances

    Annu Rev Immunol

    (2005)
  • J.S. Marshall

    Mast-cell responses to pathogens

    Nat Rev Immunol

    (2004)
  • M.J. Nadler et al.

    Signal transduction by the high-affinity immunoglobulin E receptor FcɛRI: coupling form to function

    Adv Immunol

    (2000)
  • A.M. Gilfillan et al.

    Integrated signalling pathways for mast-cell activation

    Nat Rev Immunol

    (2006)
  • C. Torigoe et al.

    An unusual mechanism for ligand antagonism

    Science

    (1998)
  • C. Gonzalez-Espinosa et al.

    Preferential signaling and induction of allergy-promoting lymphokines upon weak stimulation of the high affinity IgE receptor on mast cells

    J Exp Med

    (2003)
  • M. Daeron

    Fc receptor biology

    Annu Rev Immunol

    (1997)
  • H.M. Cherwinski et al.

    The CD200 receptor is a novel and potent regulator of murine and human mast cell function

    J Immunol

    (2005)
  • I. Bachelet et al.

    The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells

    J Immunol

    (2005)
  • K. Yotsumoto et al.

    [A novel immune receptor family, MAIR-I and II, involved in positive and negative regulation of innate immunity]

    Tanpakushitsu Kakusan Koso

    (2002)
  • T. Uehara et al.

    Inhibition of IgE-mediated mast cell activation by the paired Ig-like receptor PIR-B

    J Clin Invest

    (2001)
  • L.L. Wang et al.

    Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B

    J Immunol

    (1999)
  • R. Xu et al.

    SH2 domain-containing inositol polyphosphate 5′-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen

    J Immunol

    (2001)
  • V.S. Pribluda et al.

    Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation

    Proc Natl Acad Sci U S A

    (1994)
  • E.D. Sheets et al.

    Critical role for cholesterol in Lyn-mediated tyrosine phosphorylation of FcɛRI and their association with detergent-resistant membranes

    J Cell Biol

    (1999)
  • Cited by (0)

    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner, MD

    Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

    View full text