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• W2118649335 abstract "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. 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. In recent years, there has been a growing realization that the mast cell is a key component of innate immunity and can serve to amplify adaptive immunity.1Galli S.J. Kalesnikoff J. Grimbaldeston M.A. Piliponsky A.M. Williams C.M. Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: recent advances.Annu Rev Immunol. 2005; 23: 749-786Crossref PubMed Scopus (1059) Google Scholar, 2Marshall J.S. Mast-cell responses to pathogens.Nat Rev Immunol. 2004; 4: 787-799Crossref PubMed Scopus (669) Google Scholar Mast cells can respond to pathogens, such as bacteria and viruses, through multiple Toll-like receptors expressed on their cell surface. These receptors, for the most part, fail to elicit the hallmark response of release of preformed inflammatory mediators stored in granules but instead cause the induction of de novo cytokine production.2Marshall J.S. Mast-cell responses to pathogens.Nat Rev Immunol. 2004; 4: 787-799Crossref PubMed Scopus (669) Google Scholar Mast cells also can mediate immunity through the binding of antigen-specific Igs.3Nadler M.J. Matthews S.A. Turner H. Kinet J.P. Signal transduction by the high-affinity immunoglobulin E receptor FcɛRI: coupling form to function.Adv Immunol. 2000; 76: 325-355Crossref PubMed Google Scholar, 4Blank U. Rivera J. The ins and outs of IgE-dependent mast cell exocytosis.Trends Immunol. 2004; 25: 266-273Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 5Gilfillan A.M. Tkaczyk C. Integrated signalling pathways for mast-cell activation.Nat Rev Immunol. 2006; 6: 218-230Crossref PubMed Scopus (742) Google Scholar This plays a significant role in the ability to combat certain parasitic infections, an important role of mast cells in adaptive immunity. This dual role suggests that dysregulation of mast cell function could have untoward physiologic consequences. A clue for the necessity of controlling mast cell activation is provided by the evolution of multiple cell-surface receptors that can activate, as well as inhibit, mast cell activation.6Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref Scopus (81) Google Scholar Additional evidence for this concept is provided by studies conducted in murine models, as well as clinical studies, that demonstrate that mast cell dysregulation can cause disorders ranging from mastocytosis to autoimmunity and allergy.1Galli S.J. Kalesnikoff J. Grimbaldeston M.A. Piliponsky A.M. Williams C.M. Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: recent advances.Annu Rev Immunol. 2005; 23: 749-786Crossref PubMed Scopus (1059) Google Scholar Although the role of the mast cell in a given disease might differ, the underlying mechanism is that aberrant regulation or persistent stimuli cause unwanted mast cell activation and responses.Appropriate activation of mast cells is mediated by a number of factors, including the cells' ability to distinguish activating or inhibitory stimuli1Galli S.J. Kalesnikoff J. Grimbaldeston M.A. Piliponsky A.M. Williams C.M. Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: recent advances.Annu Rev Immunol. 2005; 23: 749-786Crossref PubMed Scopus (1059) Google Scholar and the strength and duration of the stimulus.7Torigoe C. Inman J.K. Metzger H. An unusual mechanism for ligand antagonism.Science. 1998; 281: 568-572Crossref Scopus (135) Google Scholar, 8Gonzalez-Espinosa C. Odom S. Olivera A. Hobson J.P. Martinez M.E. Oliveira-Dos-Santos A. 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; 197: 1453-1465Crossref PubMed Scopus (134) Google Scholar Multiple cell-surface receptors that contain immunoreceptor tyrosine–based inhibitory motifs (ITIMs) provide inhibitory signals to counter stimuli that can activate mast cells.6Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref Scopus (81) Google Scholar Such receptors include the low-affinity IgG receptor (FcγRIIb),9Daeron M. Fc receptor biology.Annu Rev Immunol. 1997; 15: 203-204Crossref Scopus (1031) Google Scholar CD200R,10Cherwinski H.M. Murphy C.A. Joyce B.L. Bigler M.E. Song Y.S. Zurawski S.M. et al.The CD200 receptor is a novel and potent regulator of murine and human mast cell function.J Immunol. 2005; 174: 1348-1356Google Scholar the 49-kd surface glycoprotein,11Lu-Kuo J.M. Joyal D.M. Austen K.F. Katz H.R. gp49B1 inhibits IgE-initiated mast cell activation through both immunoreceptor tyrosine-based inhibitory motifs, recruitment of src homology 2 domain-containing phosphatase-1, and suppression of early and late calcium mobilization.J Biol Chem. 1999; 274: 5791-5796Crossref Scopus (68) Google Scholar the Ig-like receptor p60,12Bachelet I. Munitz A. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells.J Immunol. 2005; 175: 7989-7995Google Scholar the myeloid-associated Ig-like receptor,13Yotsumoto K. Shibuya A. [A novel immune receptor family, MAIR-I and II, involved in positive and negative regulation of innate immunity].Tanpakushitsu Kakusan Koso. 2002; 47: 2123-2126Google Scholar mast cell function–associated antigen,14Abramson J. Pecht I. Clustering the mast cell function-associated antigen (MAFA) leads to tyrosine phosphorylation of p62Dok and SHIP and affects RBL-2H3 cell cycle.Immunol Lett. 2002; 82: 23-28Crossref PubMed Scopus (26) Google Scholar and the paired Ig-like receptor B.15Uehara T. Blery M. Kang D.W. Chen C.C. Ho L.H. Gartland G.L. et al.Inhibition of IgE-mediated mast cell activation by the paired Ig-like receptor PIR-B.J Clin Invest. 2001; 108: 1041-1050Crossref Scopus (69) Google Scholar Ligation or coligation of these receptors with FcɛRI results in downregulation of FcɛRI-mediated mast cell activation.6Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref Scopus (81) Google Scholar The common feature of these inhibitory receptors is their ITIM-dependent association with tyrosine or lipid phosphatases, which mediate their inhibitory function. However, the ITIMs expressed within specific receptors appear to display selectivity for the individual classes of phosphatases. For example, whereas the 49-kd surface glycoprotein appears to exert its inhibitory effect on mast cell activation by recruiting the tyrosine phosphatases, SH2 domain–containing phosphatase 1/2 (SHP) 1 and SHP-2,16Wang L.L. Blasioli J. Plas D.R. Thomas M.L. Yokoyama W.M. Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B.J Immunol. 1999; 162: 1318-1323Google Scholar FcγRIIb, and mast cell function–associated antigen receptors appear to do so by recruiting the inositol phosphatases SH2 domain–containing 5′-inositol phosphatase (SHIP) 1 and SHIP-2.17Malbec O. Schmitt C. Bruhns P. Krystal G. Fridman W.H. Daeron M. Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcγRIIB.J Biol Chem. 2001; 276: 30381-30391Crossref PubMed Scopus (30) Google Scholar, 18Xu R. Abramson J. Fridkin M. Pecht I. 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; 167: 6394-6402Google Scholar Mention should also be made that mast cell function can be downregulated by receptors that do not possess ITIMs. In this respect β2-adrenergic receptors effectively inhibit antigen-dependent mast cell activation after engagement of a cyclic AMP–regulated inhibitory pathway.19Shichijo M. Inagaki N. Kimata M. Serizawa I. Saito H. Nagai H. Role of cyclic 3′,5′-adenosine monophosphate in the regulation of chemical mediator release and cytokine production from cultured human mast cells.J Allergy Clin Immunol. 1999; 103: S421-S428Abstract Full Text Full Text PDF Scopus (39) Google ScholarFurther complexity is introduced by the varied functions of diverse signaling proteins that associate with or are influenced by immunoreceptor tyrosine-based activation motif (ITAM) signaling. In general, activation of kinases and phosphatases, adaptor proteins, lipid kinases and phosphatases, and lipases by ITAM-bearing receptors results in a combination of both positive and negative signals that are essential in fine tuning the cell response. Much of what is known results from studies focused on IgE/allergen-mediated stimulation through the high-affinity receptor for IgE (FcɛRI) on mast cells. Here we concentrate on events most proximal to stimulation of this receptor.FcɛRI structure and function: ITAMs as positive and negative regulatory motifsThe FcɛRI expressed on mast cells and basophils is a tetrameric receptor4Blank U. Rivera J. The ins and outs of IgE-dependent mast cell exocytosis.Trends Immunol. 2004; 25: 266-273Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar 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 module20Lin S. Cicala C. Scharenberg A.M. Kinet J.-P. The FcɛRIβ subunit functions as an amplifier of FcɛRIγ-mediated cell activation signals.Cell. 1996; 85: 985-995Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar for this receptor, and in its absence the receptor initiates weak signals. The γ chain homodimer imparts signaling competence to this receptor.4Blank U. Rivera J. The ins and outs of IgE-dependent mast cell exocytosis.Trends Immunol. 2004; 25: 266-273Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar Both the β and γ chains contain the ITAM motifs demonstrated to be essential for the amplifying and signaling competence of these receptor chains (Fig 1). The FcɛRIβ ITAM possesses a noncanonical tyrosine residue that is situated between the 2 canonical tyrosines found in conventional ITAMs. Phosphorylation of the tyrosine residues in these motifs occurs through transphosphorylation by the Src family protein tyrosine kinase (Src PTK) Lyn, and normal phosphorylation requires the liquid-ordered phase of membranes (lipid rafts) where this kinase is concentrated.21Pribluda V.S. Pribluda C. Metzger H. Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation.Proc Natl Acad Sci U S A. 1994; 91: 11246-11250Crossref Scopus (173) Google Scholar, 22Sheets E.D. Holowka D. Baird B. Critical role for cholesterol in Lyn-mediated tyrosine phosphorylation of FcɛRI and their association with detergent-resistant membranes.J Cell Biol. 1999; 145: 877-887Crossref Scopus (286) Google Scholar Once phosphorylated, novel binding sites are created where other signaling proteins can bind and propagate signals required for mast cell effector responses.4Blank U. Rivera J. The ins and outs of IgE-dependent mast cell exocytosis.Trends Immunol. 2004; 25: 266-273Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar It has been demonstrated that both the β and γ chains function to generate positive signals that are key in initiating and amplifying the mast cells' effector responses. However, recent evidence suggests that these 2 chains can also function to negatively regulate cell activation and effector responses.New insights on FcɛRIβ functionPolymorphisms in the coding region of the amplifying FcɛRIβ have been associated with allergy and asthma.23Shirakawa T. Li A. Dubowitz M. Dekker J.W. Shaw A.E. Faux J.A. et al.Association between atopy and variants of the β subunit of the high-affinity immunoglobulin E receptor.Nat Genet. 1994; 7: 125-129Crossref PubMed Scopus (384) Google Scholar, 24Laprise C. Boulet L.P. Morissette J. Winstall E. Raymond V. Evidence for association and linkage between atopy, airway hyper-responsiveness, and the β subunit Glu237Gly variant of the high-affinity receptor for immunoglobulin E in the French-Canadian population.Immunogenetics. 2000; 51: 695-702Crossref PubMed Scopus (35) Google Scholar, 25Nagata H. Mutoh H. Kumahara K. Arimoto Y. Tomemori T. Sakurai D. et al.Association between nasal allergy and a coding variant of the FcɛRIβ gene Glu237Gly in a Japanese population.Hum Genet. 2001; 109: 262-266Crossref PubMed Scopus (44) Google Scholar How these amino acid changes affect FcɛRI function and mast cell physiology is not well understood. One might envision that the change in amino acid composition might augment mast cell functional responses. However, this has not been supported by studies in which FcɛRIβ-null cells or mice were reconstituted with polymorphic FcɛRIβ and a limited analysis of mast cell responses were performed.26Furumoto Y. Hiraoka S. Kawamoto K. Masaki S. Kitamura T. Okumura K. et al.Polymorphisms in FcɛRIβ chain do not affect IgE-mediated mast cell activation.Biochem Biophys Res Commun. 2000; 273: 765-771Crossref Scopus (32) Google Scholar, 27Donnadieu E, Cookson WO, Jouvin MH, Kinet J,-P. Allergy-associated polymorphisms of the FcɛRIβ subunit do not impact its two amplification functions. J Immunol 2000;165:3917-22.Google Scholar Mutational analysis of the tyrosine residues in the ITAM of this subunit, however, has revealed several unexpected features. First, the loss of phosphorylation of Y219 alone caused a marked reduction of receptor-associated Lyn (Fig 1),28On M. Billingsley J.M. Jouvin M.H. Kinet J.P. Molecular dissection of the FcRβ signaling amplifier.J Biol Chem. 2004; 279: 45782-45790Crossref Scopus (40) Google Scholar suggesting that the other canonical tyrosine residue (Y229) is not required for FcɛRIβ interaction with Lyn. Second, loss of phosphorylation of Y219 caused a markedly delayed and diminished calcium response associated with partially inhibited mast cell degranulation and cytokine production.28On M. Billingsley J.M. Jouvin M.H. Kinet J.P. Molecular dissection of the FcRβ signaling amplifier.J Biol Chem. 2004; 279: 45782-45790Crossref Scopus (40) Google Scholar, 29Furumoto Y. Nunomura S. Terada T. Rivera J. Ra C. The FcɛRIβ; immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IκB kinase phosphorylation and mast cell cytokine production.J Biol Chem. 2004; 279: 49177-49187Crossref PubMed Scopus (95) Google Scholar Third, unexpectedly, mutation of the noncanonical tyrosine (Y225) caused a marked increase in mast cell cytokine production (IL-6 and IL-13) without affecting mast cell degranulation or leukotriene C4 production.29Furumoto Y. Nunomura S. Terada T. Rivera J. Ra C. The FcɛRIβ; immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IκB kinase phosphorylation and mast cell cytokine production.J Biol Chem. 2004; 279: 49177-49187Crossref PubMed Scopus (95) Google Scholar This was associated with decreased tyrosine phosphorylation of SHIP-1. Importantly, activation of nuclear factor κB was found to be augmented by mutation of Y225, indicating that this residue plays an important role in negative regulation of this transcription factor. Interestingly, mutation of both canonical tyrosines (Y219/Y229) resulted in reduced, but not ablated, binding of SHIP-1 and the p85 regulatory subunit of phosphatidylinositol 3-OH kinase (PI3K), suggesting that Y225 might also be important for SHIP-1 and PI3K interactions.29Furumoto Y. Nunomura S. Terada T. Rivera J. Ra C. The FcɛRIβ; immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IκB kinase phosphorylation and mast cell cytokine production.J Biol Chem. 2004; 279: 49177-49187Crossref PubMed Scopus (95) Google Scholar Thus it appears that the FcɛRIβ ITAM can promote negative signals that affect mast cell responses. Interestingly, a recent study by Xiao et al30Xiao W. Nishimoto H. Hong H. Kitaura J. Nunomura S. Maeda-Yamamoto M. et al.Positive and negative regulation of mast cell activation by Lyn via the FcɛRI.J Immunol. 2005; 175: 6885-6892PubMed Google Scholar promotes the view that the strength of the stimulus determines whether FcɛRIβ serves as a positive or negative regulator. This study demonstrates that under a low-intensity stimulus, the FcɛRIβ functions to amplify responses, whereas at a high intensity of stimulus, it might exert a negative regulatory role.A new role for FcɛRIγIn addition to FcɛRIβ, recent studies also extend a negative regulatory role to FcɛRIγ.31Pasquier B. Launay P. Kanamaru Y. Moura I.C. Pfirsch S. Ruffie C. et al.Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM.Immunity. 2005; 22: 31-42Abstract PubMed Scopus (283) Google Scholar Engagement of FcαRI, a receptor that uses FcɛRIγ for cell activation, was similarly found to inhibit FcɛRI-dependent mast cell degranulation.31Pasquier B. Launay P. Kanamaru Y. Moura I.C. Pfirsch S. Ruffie C. et al.Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM.Immunity. 2005; 22: 31-42Abstract PubMed Scopus (283) Google Scholar This response, which was mediated through the association of FcɛRIγ with FcαRI and required an intact phospho-ITAM, was seemingly fostered by association with the phosphatase SHP-1 (Fig 1). Collectively, these studies alter the view of ITAMs as solely positive effectors in immune cell activation and indicate that the context in which ITAMs are engaged might determine whether they function to activate or inhibit responses.Regulation by receptor-proximal tyrosine kinasesFcɛRI-mediated activation of mast cells requires both Lyn and the related Src PTK Fyn (Fig 2) as receptor-proximal kinases.32Parravicini V. Gadina M. Kovarova M. Odom S. Gonzalez-Espinosa C. Furumoto Y. et al.Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation.Nat Immunol. 2002; 3: 741-748Crossref PubMed Scopus (400) Google Scholar 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,33Kawakami Y. Kitaura J. Satterthwaite A.B. Kato R.M. Asai K. Hartman S.E. et al.Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.J Immunol. 2000; 165: 1210-1219Crossref Scopus (151) Google Scholar, 34Hernandez-Hansen V. Smith A.J. Surviladze Z. Chigaev A. Mazel T. Kalesnikoff J. et al.Dysregulated FcɛRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells.J Immunol. 2004; 173: 100-112Crossref Scopus (103) Google Scholar, 35Gomez G. Gonzalez-Espinosa C. Odom S. Baez G. Cid M.E. Ryan J.J. et al.Impaired FcɛRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn-deficiency in mast cells.J Immunol. 2005; 175: 7602-7610PubMed Google Scholar 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 required for normal mast cell activation.32Parravicini V. Gadina M. Kovarova M. Odom S. Gonzalez-Espinosa C. Furumoto Y. et al.Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation.Nat Immunol. 2002; 3: 741-748Crossref PubMed Scopus (400) Google Scholar, 35Gomez G. Gonzalez-Espinosa C. Odom S. Baez G. Cid M.E. Ryan J.J. et al.Impaired FcɛRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn-deficiency in mast cells.J Immunol. 2005; 175: 7602-7610PubMed Google Scholar However, in the absence of Lyn, Fyn and the related Hck and Fgr (Yamashita et al, unpublished observation) are not responsible for the phosphorylation of FcɛRI.35Gomez G. Gonzalez-Espinosa C. Odom S. Baez G. Cid M.E. Ryan J.J. et al.Impaired FcɛRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn-deficiency in mast cells.J Immunol. 2005; 175: 7602-7610PubMed Google Scholar Thus for the moment it is unclear what other kinase can phosphorylate FcɛRI, but Src family kinase activity is clearly essential for Lyn-independent FcɛRI-mediated mast cell activation because ITAM-null FcɛRI and Lyn-null mast cells treated with the Src selective inhibitor PP2 failed to degranulate.36Odom S. Gomez G. Kovarova M. Furumoto Y. Ryan J.J. Wright H.V. et al.Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.J Exp Med. 2004; 199: 1491-1502Crossref Scopus (182) Google ScholarFig 2Simplified scheme of FcɛRI signaling events in mast cells. Engagement of FcɛRI results in inclusion in lipid rafts, phosphorylation (P) of receptor ITAMs by Lyn kinase, and activation of Syk kinase through ITAM binding. Fyn kinase is also activated and is important for phosphorylation of the adapter known as Gab2 and activation of PI3K activity. Lyn regulates the activation of Syk and phosphorylation of several adaptor proteins called LAT and NTAL. These proteins function as scaffolds and organize other signaling proteins that can affect Ras activation, PLCγ activation through the coordinated function of Gads/SLP-76/Vav1 and Tec family kinases, PI3K activity, and calcium responses. PLCγ activation can also be regulated independently of LAT through a PI3K/Btk-dependent pathway. MAP kinase and transcription factor activation is dependent on LAT (and possibly NTAL) leading to mast cell cytokine production and eicosanoid production through cPLA2 activation. PLCγ-generated DAG is key for early activation of PKC and mast cell cytokine production and degranulation. PI3K activity is also required for activation of PLD and SphK1. SphK generates S1P from sphingosine (Sph), which influences calcium mobilization and mast cell effector responses through cell-surface receptors for S1P (see text). The coordination of these molecular events is intrinsically regulated by both positive and negative functions of many of the components in the signaling cascade.View Large Image Figure ViewerDownload (PPT)Whether Lyn interactions with FcɛRI are essential for mast cell degranulation remains somewhat controversial because various studies have demonstrated a reduced response,29Furumoto Y. Nunomura S. Terada T. Rivera J. Ra C. The FcɛRIβ; immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IκB kinase phosphorylation and mast cell cytokine production.J Biol Chem. 2004; 279: 49177-49187Crossref PubMed Scopus (95) Google Scholar, 37Hibbs M.L. Tarlinton D.M. Armes J. Grail D. Hodgson G. Maglitto R. et al.Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease.Cell. 1995; 83: 301-311Abstract Full Text PDF PubMed Scopus (616) Google Scholar a normal response,33Kawakami Y. Kitaura J. Satterthwaite A.B. Kato R.M. Asai K. Hartman S.E. et al.Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.J Immunol. 2000; 165: 1210-1219Crossref Scopus (151) Google Scholar, 38Nishizumi H. Yamamoto T. Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in Lyn-deficient bone marrow-derived mast cells.J Immunol. 1997; 158: 2350-2355Google Scholar or an enhanced response.34Hernandez-Hansen V. Smith A.J. Surviladze Z. Chigaev A. Mazel T. Kalesnikoff J. et al.Dysregulated FcɛRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells.J Immunol. 2004; 173: 100-112Crossref Scopus (103) Google Scholar, 36Odom S. Gomez G. Kovarova M. Furumoto Y. Ryan J.J. Wright H.V. et al.Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.J Exp Med. 2004; 199: 1491-1502Crossref Scopus (182) Google Scholar One possible explanation for the apparent discrepancies is the genetic background of the mice and mast cells derived thereof. For example, it has been demonstrated that the SV129 strain, most commonly used to generate a genetically altered mouse, is skewed toward dominant TH2 responses, whereas the C57/BL6 strain, the most common strain used for backcrossing SV129 mice for effective breeding, is skewed toward TH1 responses.39Beavitt S.J. Harder K.W. Kemp J.M. Jones J. Quilici C. Casagranda F. et al.Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity.J Immunol. 2005; 175: 1867-1875Google Scholar Thus the effects of a particular genetic deletion are likely to be influenced by the complex genetic makeup of the strain used. In most studies published to date, the mice or mast cells thereof are of mixed background (SV129 and C57/BL6). Regardless, all studies demonstrate that the loss of Lyn does not completely ablate mast cell degranulation, and thus one can conclude that other early signals, which function independently of Lyn, are required to drive normal mast cell degranulation.Relationship of Fyn and Lyn with Syk kinaseConsiderable evidence has accumulated in support of FcɛRI-mediated and Lyn-dependent activation of Syk (Fig 2).40Kihara H. Siraganian R.P. Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor.J Biol Chem. 1994; 269: 22427-22432Abstract Full Text PDF Google Scholar, 41Jouvin M.-H.E. Adamczewski M. Numerof R. Letourneur O. Valle A. Kinet J.-P. 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: 5918-5925Abstract Full Text PDF Google Scholar Lyn-null bone marrow–derived mast cells (BMMCs) showed a severe defect in the onset and extent of FcɛRI-mediated Syk activation.32Parravicini V. Gadina M. Kovarova M. Odom S. Gonzalez-Espinosa C. Furumoto Y. et al.Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation.Nat Immunol. 2002; 3: 741-748Crossref PubMed Scopus (400) Google Scholar, 33Kawakami Y. Kitaura J. Satterthwaite A.B. Kato R.M. Asai K. Hartman S.E. et al.Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.J Immunol. 2000; 165: 1210-1219Crossref Scopus (151) Google Scholar, 38Nishizumi H. Yamamoto T. Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in Lyn-deficient bone marrow-derived mast cells.J Immunol. 1997; 158: 2350-2355Google Scholar However, the relationship between Fyn and Syk in mast cells remains enigmatic. The loss of Syk in mast cells results in a severe FcɛRI-nonresponsive phenotype,42Costello P.S. Turner M. Walters A.E. Cunningham C.N. Bauer P.H. Downward J. et al.Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells.Oncogene. 1996; 13: 2595-2605PubMed Google Scholar but it is not known whether Fyn is active or inactive under these conditions. Recently, it has been proposed that Fyn is required for optimal activation of Syk.43Yu M. Lowell C.A. Neel B.G. Gu H. Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcɛRI.J Immunol. 2006; 176: 2421-2429PubMed Google Scholar If so, this places Fyn upstream of Syk activation (Fig 2). However, inactivation of Fyn had no detectable effects on the phosphorylation of Syk substrates (eg, the linker for activation of T cells [LAT] or the guanine nucleotide exchange factor Vav135Gomez" @default.
• W2118649335 created "2016-06-24" @default.
• W2118649335 creator A5044874326 @default.
• W2118649335 creator A5059179977 @default.
• W2118649335 date "2006-06-01" @default.
• W2118649335 modified "2023-10-11" @default.
• W2118649335 title "Molecular regulation of mast cell activation" @default.
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