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MINIREVIEW Tec family kinases: regulation of FceRI-mediated mast-cell activation Wilfried Ellmeier, Anastasia Abramova and Alexandra Schebesta Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria Keywords cytokine production; degranulation; earlyphase and late-phase effector functions; Itk; mast cell signaling; Tec; TLR activation; type I hypersensitivity reactions; tyrosine kinases Correspondence W Ellmeier, Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Lazarettgasse 19, 1090 Vienna, Austria Fax: +43 40160 965003 Tel: +43 40160 65003 E-mail: wilfried.ellmeier@meduniwien.ac.at Mast cells express the high-affinity receptor for IgE (FceRI) and are key players in type I hypersensitivity reactions They are critically involved in the development of allergic rhinitis, allergic asthma and systemic anaphylaxis, however, they also regulate normal physiological processes that link innate and adaptive immune responses Thus, their activation has to be tightly controlled One group of signaling molecules that are activated upon FceRI stimulation is formed by Tec family kinases, and three members of this kinase family (Btk, Itk and Tec) are expressed in mast cells Many studies have revealed important functions of Tec kinases in signaling pathways downstream of the antigen receptors in lymphocytes This review summarizes the current knowledge about the function of Tec family kinases in FceRI-mediated signaling pathways in mast cell (Received 31 August 2010, revised November 2010, accepted 25 February 2011) doi:10.1111/j.1742-4658.2011.08073.x Mast cells are crucial regulators of type I hypersensitivity reactions Mast cells are key players in type I hypersensitivity reactions and are critically involved in the development of allergic rhinitis, allergic asthma and systemic anaphylaxis Mast cells (as well as basophils) express the high-affinity Fc receptor type I for IgE (FceRI), and thus one of their most characteristic features is their ability to bind IgE Cross-linking of the IgE ⁄ FceRI complex with antigen (e.g an allergen) causes the activation of mast cells and induces a variety of effector functions As a part of the early-phase response that occurs within minutes, mast cells secrete preformed mediators like histamine, proteolytic enzymes and proteoglycans In addition, rapidly synthesized lipid mediators such as leukotrienes (LTs) and prostaglandins Abbreviations BMMC, bone marrow-derived mast cells; Btk, Bruton’s tyrosine kinase; Bmx, bone marrow kinase on the X chromosome; Erk, extracellular signal-regulated kinase; FceRI, high-affinity Fc receptor type I for IgE; Grb2, growth factor receptor bound 2; IL, interleukin; Itk, IL-2-inducible T-cell kinase; JNK, c-jun N-terminal kinase; LAT, linker for the activation of T cells; LT, leukotriene; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor for activated T cells; NFjB, nuclear factor kappa-light chain enhancer of activated B cells; PDK1, 3-phosphoinositidedependent protein kinase 1; PH, pleckstrin homology; PK, protein kinase; PLC, phospholipase C; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns(4,5)P3, phosphatidylinositol-4,5-bisphosphate; Rlk, resting lymphocyte kinase; Src, sarcoma; Syk, spleen tyrosine kinase; Tec, tyrosine kinase expressed in hepatocellular carcinoma; TFK, Tec family kinase; TNF, tumor necrosis factor; TLR, Toll-like receptor; xid, X-linked immunodeficiency; ZAP-70, zeta-chain-associated kinase 70 1990 FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS W Ellmeier et al are released within a short time after activation Moreover, mast-cell activation leads to the production of various cytokines and chemokines This occurs within hours after activation and is a part of the late-phase response The plethora of mediators and factors produced in the early- and late-phase activation by mast cells cause many physiological and pathophysiological changes associated with type I hypersensitivity reactions These include vasodilation and increased vascular permeability, and functional changes that are dependent on the affected tissues such as enhanced mucus production, bronchoconstriction, diarrhea and vomitting, as well as the infiltration of many other types of immune cells, such as eosinophils, basophils, monocytes, neutrophils and lymphocytes [1,2] In addition to their crucial role in type I hypersensitivity reactions, mast cells can also be activated by IgE-independent triggers such as FccR or complement receptors [3] Moreover, mast cells express a variety of Toll-like receptors (TLRs) and it has been shown that mast cells can contribute to the host defense against bacterial infections [4,5] Furthermore, mast cells have been implicated in the defense against toxins, but also in the pathology of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease, in cardiovascular diseases and in cancer [6] Thus, mast cells are not only critically involved in type I hypersensitivity reactions, but they also have to be considered an important positive as well as negative regulator of normal physiological processes that link innate and adaptive immune responses [7] It has been shown that mast cells originate from CD13+CD34+CD117+ hematopoietic bone marrow progenitor cells [8–10] Mast cells are most abundant in the gut, skin and airways, and mature in tissues from their committed progenitors [11] Dependent on the microenvironment of the surrounding tissue, or on the conditions under which they have been generated in vitro, mast cells acquire distinct phenotypic profiles and thus produce different types of early- and latephase mediators Moreover, there are differences between murine and human mast cells [12] These issues have to be taken into account when comparing data obtained from different studies Mast-cell activation pathways The signaling pathways that regulate the activation of mast cells upon FceRI cross-linking have been investigated in great detail Many of the signaling molecules that have important functions in FceRI signaling pathways are also expressed in lymphocytes, thus there are similarities in the basic signaling Tec kinases in mast cells machinery of the FceRI in mast cells and antigen receptors in lymphocytes Several recent reviews have comprehensively summarized FceRI-mediated signaling in mast cells [13–15], therefore the key steps in the activation of mast cells are only briefly described in this review The FceRI is a multimeric cell surface receptor consisting of an a, b and two c chains The a chain binds IgE, whereas the b and c chains are involved in the signal transduction [16] One of the earliest steps after FceRI cross-linking is the tyrosine phosphorylation of several cellular proteins, including immunoreceptor tyrosine-based activation motifs in the FceRI b and c chains (Fig 1) This leads to the recruitment and activation of the sarcoma (Src) family kinase Lyn, and subsequently to the activation of spleen tyrosine kinase (Syk), a member of the Syk ⁄ zeta-chain-associated kinase 70 (ZAP-70) kinase family This results in the phosphorylation of linker for the activation of T cells (LAT) and the formation of a large signaling complex that also contains Bruton’s tyrosine kinase (Btk) Subsequently, Syk and Btk activate phospholipase C (PLC)c1 and PLCc2, which convert phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P3] into inositol-1,4,5-trisphosphate and diacylglycerol, leading to Ca2+ mobilization and the activation of protein kinase (PK)C isoforms Formation of the LAT signaling complex leads also to activation of the mitogen-activated protein kinase (MAPK) pathways Ca2+ mobilization and MAPK activation lead to the activation of downstream transcription factors required for cytokine expression such as members of the nuclear factor for activated T cells (NFAT) family and of the activator protein-1 complex, respectively A complementary signaling pathway that is also required for the activation of mast cells is mediated by Fyn, another member of the Src kinase family [17] Fyn associates with the FceRI b chain, and activates the adaptor protein Grb2-associated binding protein 2, which is a positive effector molecule for the activation of the phosphatidylinositol 3-kinase (PtdIns3K) pathway This leads to membrane recruitment of pleckstrin homology (PH) domain containing signaling molecules such as 3-phosphoinositide-dependent protein kinase (PDK1) and PKB ⁄ Akt Activation of PDK1 is important for degranulation, and activated PKB ⁄ Akt leads to the activation of the nuclear factor kappa-light chain enhancer of activated B cells (NFjB) pathway, essential for the induction of cytokine expression Thus, both Lyn- and Fyn-mediated pathways are required for efficient mast-cell activation Together, this complex signaling network downstream of the FceRI induces the various mast-cell responses, ranging from earlyphase effector function such as degranulation and the FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS 1991 Tec kinases in mast cells W Ellmeier et al Fig A simplified scheme of FceRI signaling IgE ⁄ FceRI cross-linking by antigen induces the phosphorylation of immunoreceptor tyrosine-based activation motifs in the FceRI b and c chains This leads to the recruitment and activation of the Src family kinase Lyn, which activates Syk, a member of the Syk ⁄ ZAP-70 kinase family This results in the phosphorylation of several tyrosine residues in LAT and the formation of a signaling complex containing the guanine nucleotide exchange factor Vav and adaptor molecules such as Src homology 2-domain containing leukocyte protein of 76 kDa, growth factor receptor bound (Grb2), Grb2-related adaptor protein (Gab2), kinases such as Btk and PLCc (PLCc1 and PLCc2) Btk recruitment to the membrane is regulated via PH domain-mediated binding to PtdIns(3,4,5)P3 binding, generated by activated PtdIns3K Syk and Btk activate PLCc1 and PLCc2, which convert PtdIns(4,5)P2 into inositol-1,4,5-trisphosphate and diacylglycerol, leading to Ca2+ mobilization and the activation of PKC isoforms FceRI cross-linking leads also to the activation, via Grb2 ⁄ son of sevenless (SOS) of the MAPK Erk1 ⁄ 2, p38 and JNK1 ⁄ Together, the signals lead to the activation of transcription factors such as of the NFAT and activator protein-1 gene families The association of Fyn, another member of the Src kinase family, with the FceRI b chain induces a complementary signaling pathway required for efficient mast-cell activation Fyn activates the adaptor protein Grb2-associated binding protein 2, which activates PtdIns3K, leading to the generation of PtdIns(3,4,5)P3 from PtdIns(4,5)P2 and subsequently to PH domain-mediated recruitment of PDK1 and PKB ⁄ Akt PDK1 activation leads to degranulation (via the activation of PKCd) PKB ⁄ Akt signaling leads to activation of the NFjB pathway Together, this complex signaling network downstream of the FceRI leads to the activation of various mast-cell responses, ranging from early-phase effector function, such as degranulation and the production of lipid mediators, to late-phase effector function, such as cytokine production Btk is required for efficient PLCc activation, and loss of Btk leads to impaired Ca2+ mobilization and impaired early- and late-phase effector functions Tec positively regulates cytokine production and lipid mediator production, although it negatively regulates Erk ⁄ activation Itk is a negative regulator of cytokine production The role of Rlk in mast cells is not known For simplicity, not all cross-talks between the various signaling molecules and pathways are indicated DAG, diacylglycerol; IP3, inositol-1,4,5-triphosphate production of lipid mediators to late-phase effector function such as the production of various cytokines A brief overview of Tec family kinases As described above, FceRI signaling pathways have been investigated in great detail Studies using mast cells generated from mice deficient in the Src family kinase 1992 members Lyn [18–20] or Fyn [17], or from mice which lack the Syk ⁄ ZAP-70 kinase family member Syk [21] have convincingly demonstrated a critical role of these two kinase families during mast-cell activation Tec family kinases (TFKs) represent another class of protein tyrosine kinases that are implicated in FceRI-mediated mast-cell activation [22] The Tec kinase family constitutes the second largest family of nonreceptor protein FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS W Ellmeier et al tyrosine kinases and consists of five members [23]: bone marrow kinase on the X chromosome (Bmx; also known as Etk) [24–26], Btk [27–29], interleukin (IL)-2inducible T-cell kinase (Itk; also known as Emt) [24,30,31], resting lymphocyte kinase (Rlk; also known as Txk) [32,33] and tyrosine kinase expressed in hepatocellular carcinoma (Tec) [34] They are preferentially expressed in cells of the immune system, although expression of some members outside the hematopoietic system has been described [25,34] Btk, Itk and Tec are expressed in mast cells and are activated upon crosslinking of FceRI [35–37], suggesting that they are part of the signaling machinery in mast cells In addition, Rlk expression has been described in mast cell lines [38] Ever since their discovery, TFKs have received a lot of attention in studies investigating signal transduction pathways in immune cells Mutations in Btk are the molecular cause of X-linked agammaglobulinemia, a rare human genetic disorder characterized by a reduction in serum Ig levels due to defects in B lymphocyte development [27,28,39] In contrast to the large number of different mutations described for the human BTK gene, a single point mutation (R28C) in the PH domain in the murine Btk gene leads to a similar, but less severe, syndrome in mice, X-linked immunodeficiency (xid) [29,40] More recently, a homozygous mutation in the Src homology domain of Itk has been linked with an Epstein Barr virus-associated lymphoproliferative disease [41] The key regulatory steps that lead to the activation of TFK have been defined by using a variety of biochemical and functional studies, as well as genetic approaches The majority of studies dissecting the activation steps have been performed in lymphocytes, which revealed that Tec kinases are regulated at various levels They are recruited to the membrane via the interaction of their PH domain with PtdIns(3,4,5)P3 phosphate, which is generated from PtdIns(4,5)P2 by PtdIns3K Upon membrane localization, they are phosphorylated by Src family kinases such as Lck or Lyn, and subsequent autophosphorylation leads to their full activation TFK form intra- and intermolecular interactions, which can regulate their activation, and Tec kinases are also part of larger signaling complexes and membrane-associated adaptor proteins Moreover, the detailed analysis of B cells isolated from X-linked agammaglobulinemia patients and xid mice, and the generation of mice deficient for Tec family members have led to a comprehensive insight into TFK-dependent biological processes induced by antigen receptor stimulation in lymphocytes These studies clearly demonstrated that TFK are important regulators of lymphocyte function Several recent reviews Tec kinases in mast cells comprehensively summarize the current knowledge about the evolution, structure, activation pathways and function of TFK in lymphocytes [39,42–47] and are therefore not described further The role of TFK in the myeloid lineage has not been studied as extensively as in the lymphoid lineage Nevertheless, studies performed in human and murine monocytes ⁄ macrophages [48–52], osteoclasts [53], dendritic cells [54], neutrophils [55,56], platelets [57] and erythroid cells [58] indicate crucial functions for TFK also in the nonlymphoid lineages of the hematopoietic system [59,60] This minireview summarizes studies describing the role of Btk, Itk and Tec in mast cells Mast-cell development in the absence of TFK Mast-cell development appears to be normal in the absence of Btk (both in Btk-null or xid mice), Tec or Itk Analysis of various types of mast cells in Btk) ⁄ ) (skin, tracheobronchial airways), Tec) ⁄ ) (skin) and Itk) ⁄ ) (skin, peritoneum, tracheobronchial airways, lung) mice showed no differences compared with wildtype mice with respect to tissue distribution, cell quantities or morphological features [37,61–63] However, ex vivo analyzed peritoneal and splenic Itk) ⁄ ) mast cells had higher levels of FceRI on their surface, most likely due to the elevated IgE serum levels in the absence of Itk [63] In vitro IL-3 or IL-3 ⁄ stem cell factor-generated Tec) ⁄ ), Btk) ⁄ ) or Itk) ⁄ ) bone marrow-derived mast cells (BMMC) showed similar histological staining characteristics and had similar expression levels of FceRI that were upregulated to comparable levels upon overnight incubation with IgE [37,61–63] However, Btk- or Tec-deficient BMMC generated in the presence of either IL-3 or IL-3 ⁄ stem cell factor yielded higher numbers of mast cells compared with wild-type cultures [37,64,65] Btk-null mast cells showed reduced cell death during BMMC culture and this might be the cause of increased cell numbers, because Btk-deficient mast cells die more slowly upon IL-3 deprivation than wild-type cells [64,65] Btk-deficient mast cells showed reduced c-Jun N-terminal kinase (JNK)1 ⁄ activation upon IL-3 withdrawal, and the impaired JNK1 ⁄ activation could be reversed by enforced retroviral expression of a wild-type, but not a kinase-dead, version of Btk in Btk-deficient mast cells, indicating an essential role for Btk kinase activity in the activation of JNK1 ⁄ [64] A side-by-side comparison of Tec- and Btk-deficient cultures (as well as Tec) ⁄ )Btk) ⁄ ) cultures) revealed that the mast cell numbers were significantly higher in Tec) ⁄ ) cultures than in Btk) ⁄ ) FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS 1993 Tec kinases in mast cells W Ellmeier et al cultures, but did not increase further in Tec) ⁄ )Btk) ⁄ ) cultures [37] The reason for the negative role of Tec in these in vitro cultures is not known Because in vivo numbers of mast cells are similar between wild-type, Tec) ⁄ ) and Btk) ⁄ ) mice, it is likely that the cytokine milieu and ⁄ or the different microenvironment in vitro leads to increased numbers of mast cells in the absence of Tec kinases Btk regulates early- and late-phase effector functions upon FceRI-mediated mast-cell activation Soon after the discovery that Btk is mutated in X-linked agammaglobulinemia ⁄ xid, studies performed by Kawakami and colleagues [61] with either xid or with gene-targeted Btk-deficient mice revealed that Btk is a crucial regulator of FceRI-mediated mast cell functions in vivo and in vitro Btk-deficient mice were subjected to various passive cutaneous anaphylaxis experiments to test early- and late-phase mast-cell effector functions In one type of passive cutaneous anaphylaxis experiment, mice were ‘sensitized’ with intradermal injection of anti-dinitrophenol IgE followed by intravenous injection of antigen (dinitrophenol–BSA) and Evans blue dye Btk-mutant mice showed a dose-dependent decrease in blood vessel permeability as measured by the extravasations of Evans blue dye shortly after antigen exposure In another passive cutaneous anaphylaxis model system, mice were intravenously injected with anti-dinitrophenol IgE followed by applying dinitrofluorobenzene to the ear of sensitized mice Btk-mutant mice displayed reduced edema, as indicated by a reduced increase in ear thickness 24 h after dinitrofluorobenzene exposure [61] Thus, both early and late effector phases are impaired in Btk-deficient mice In addition to the in vivo experiments, many studies performed with in-vitro-generated BMMCs extended the observation that Btk plays an important role in the regulation of FceRI signaling and helped to characterize in detail the biochemical and molecular function of Btk Degranulation as measured by histamine secretion is delayed ⁄ impaired in a dose-dependent manner in Btk-null mast cells [37,61,65], and the release of LTs (without distinguishing between C4 ⁄ D4 ⁄ E4) was found to be similar in control and Btk-deficient mast cells [61,65] However, more recent studies indicated that LTC4 production is reduced in BMMC in the absence of Btk [37,66] in addition to prostaglandin D2 and reactive oxygen species production [66] Biochemically, the impairment of early effector functions can be attributed, despite a normal total tyrosine phosphory1994 lation pattern, to impaired PLCc1 and PLCc2 phosphorylation and hence impaired inositol-1,4,5triphosphate generation and Ca2+ mobilization [37,61,65,66], which is important for mast cell degranulation [67,68] Other FceRI-signaling defects detected in the absence of Btk were reduced activation of JNK1 ⁄ and p38 [65,66], whereas PKCa and PKCbII phosphorylation appeared to be slightly enhanced [66] No differences in the phosphorylation ⁄ activation kinetics of Syk, FceRIb, PKB ⁄ AKT, and extracellular signal-regulated kinase (Erk) ⁄ have been reported [37,61,65,66] The signaling defects in the absence of Btk resulted in impaired activation of the transcription factors NFjB and NFAT [69], providing an explanation for the impaired but not fully abrogated secretion of inflammatory cytokines [such as IL-2, tumor necrosis factor (TNFa), IL-6, IL-13 and GM-CSF) in xid and Btk-deficient mast cells [37,61,66,69] In agreement with the observed defects in cytokine production, the promoter regions of Il2 and Tnfa show reduced activity in Btk-null compared with wild-type mast cells in transient luciferase reporter assays performed in mast cells [61] Furthermore, it has been demonstrated that Btk regulates FceRI-induced IL-2 transcription through a pathway including JNK1 ⁄ 2, activator protein-1 and NFAT, whereas Btk also positively regulates IL-2 and TNFa expression via PKB ⁄ Akt dependent pathways [61,64,70] One notable exception from the list of cytokines that were reduced in Btk-deficient mast cells is IL-4, which is enhanced in the absence of Btk [37] It is clear that Btk, dependent on the cellular context and ⁄ or type of receptor stimulation, can function as a positive and negative regulator of signaling pathways It has been demonstrated that Btk can act as either a pro- or anti-apoptotic signaling intermediate in FasL- or radiation-induced apoptosis, respectively [71,72] Moreover, it was shown that Btk-deficient murine bone marrow-derived dendritic cells were more mature and displayed an increased in vitro and in vivo T-cell stimulatory capacity compared with wild-type bone marrow-derived dendritic cells [54] Although a molecular mechanism to explain the enhanced IL-4 levels remains to be determined, the finding that Btk-deficient mast cells showed enhanced IL-4 secretion further supports the general concept that Btk can also have negative regulatory roles Another interesting Btk function was revealed by the observation that Btk plays a role in regulating mast-cell adhesion upon monomeric IgE binding [73] During recent years, it has been shown that monomeric IgE molecules not only lead to the upregulation of FceRI expression on mast cells [74,75], but that FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS W Ellmeier et al certain IgE molecules (termed highly cytokinergic IgEs) also promote the adhesion to fibronectin and the survival of mast cells [76,77] This effect is mediated via b1 and b7 integrins, and monomeric IgE–FceRImediated inside-out signaling activates Lyn, Syk and Btk Adhesion to fibronectin of Btk-deficient BMMC was partially impaired, indicating a regulatory role of Btk in this process This was specific to FceRI-mediated adhesion pathways, because stem cell factor-stimulated wild-type and Btk-deficient mast cells showed a similar adhesion [73] Itk and FceRI-mediated mast-cell activation A role for Itk in mast cells has long been suspected ever since it was shown that Itk is activated upon FceRI signaling [36] Experimental evidence for a function of Itk during mast-cell activation was initially provided by Forssell et al [62] using an ovalbumininduced acute phase plasma extravasation model that is dependent on IgE-mediated mast-cell degranulation Mice were immunized twice with ovalbumin, subsequently injected with Evans blue dye and rechallenged with aerosolized ovalbumin Under these conditions, Itk-deficient mice showed a dramatically reduced Evans blue dye extravasation compared with wild-type mice In line with this finding, it was observed that Itk) ⁄ ) airway mast cells showed a decreased degranulation response compared with wild-type airway mast cells [62] However, another study from August and colleagues [63] showed that transfer of Itk) ⁄ ) mast cells into mast cell-deficient W ⁄ Wv mice fully rescued the histamine defect of W ⁄ Wv mice in a systemic anaphylactic reaction model, in which mice were injected with anti-dinitrophenol IgE followed by systemic administration of dinitrophenol–human serum albumin Because IgE levels are elevated in Itk) ⁄ ) mice [62,78,79], it is conceivable that the reduced mast-cell responses of Itk) ⁄ ) mice in in vivo model systems were most likely due to IgE-loaded or occupied FceRI on mast cells which may impair binding of newly synthesized or administered IgE [63] A detailed phenotypic in vitro analysis of Itk) ⁄ ) BMMC showed that they have a normal degranulation response (as revealed by assaying hexosaminidase release) and Ca2+ mobilization, however, Itk-deficient BMMC produced increased levels of IL-13 and TNFa compared with wild-type BMMCs The increase in cytokine production correlated with enhanced expression of NFATc1 and NFATc2, and enhanced nuclear localization of NFATc2 already in nonstimulated Itk) ⁄ ) mast cells [63] These data indicate that Itk is dispensable for Tec kinases in mast cells degranulation, but they suggest that Itk is a crucial negative regulator of cytokine production in mast cells Tec is essential for efficient cytokine production upon FceRI-mediated mast-cell activation Tec is the third member of the Tec kinase family for which a function in mast cells could be identified Studies from our laboratory showed that Tec is activated upon FceRI stimulation, clearly indicating that Tec is a part of the signaling machinery downstream of the FceRI signalosome [37] An examination of early-phase mast cell effector function revealed that histamine release upon in vitro FceRI activation was normal in Tec) ⁄ ) BMMC Moreover, Tec-deficient mice displayed normal serum histamine levels in an anaphylactic reaction model, in which mice were primed with anti-trinitrophenol IgE followed by systemic injection of trinitrophenol Thus, unlike Btk, Tec is not controlling the release of histamine upon mastcell activation However, Tec has an essential function in pathways leading to the generation of LTC4, because LTC4 levels were severely reduced in Tec) ⁄ ) BMMC LTs are generated from arachidonic acid by the activity of 5-lipoxygenase This generates LTA4, which is converted into LTB4 or LTC4 by LTA4 hydrolase or LTC4 synthase, respectively [80] Because LTB4 levels (and thus LTA4 hydrolase activity) were comparable between Tec+ ⁄ + and Tec) ⁄ ) BMMC, Tec might specifically contribute to the regulation of LTC4 synthase activity [37] Tec is also required in BMMC for efficient cytokine production In the absence of Tec, TNFa, IL-13 and GM-CSF levels were reduced, although IL-5 and IL-6 were not affected by the loss of Tec In contrast, IL-4 production was almost completely abolished, indicating an essential role of Tec in the regulation of IL-4 Biochemically, the defects in the generation of LTC4 and in cytokine production were accompanied by mild defects in Ca2+ mobilization, although PLCc1 (Y783) and PLCc2 phosphorylation (Y1217) as well as LAT and PKB ⁄ Akt phosphorylation were similar between Tec+ ⁄ + and Tec) ⁄ ) BMMC However, activation of the MAPK pathways was altered in the absence of Tec, because JNK1 ⁄ phosphorylation was reduced, whereas p38 activation appeared to be normal Interestingly, Tec) ⁄ ) BMMC displayed enhanced Erk1 ⁄ activation upon FceRI stimulation Although a link between enhanced Erk1 ⁄ phosphorylation and a biological phenotype of Tec) ⁄ ) BMMC could not be established in this study, the results clearly demonstrate that Tec is a negative regulator of signaling FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS 1995 Tec kinases in mast cells W Ellmeier et al pathways that lead to the activation of Erk1 ⁄ in mast cells [37] Compensatory pathways among TFK in mast cells It is well documented that there are compensatory functions among members of the Tec kinase family Hence, combined deletions result in more severe phenotypes than individual deletions This has been demonstrated for Itk and Rlk in T cells [81], and for Tec and Btk in B cells [82], macrophages [51,52], osteoclasts [53] and platelets [57] Because mast cells express multiple members of Tec kinases, it was not surprising that compensatory functions have been observed for Tec and Btk in mast cells Although early-phase effector functions such as histamine release were not further reduced in Tec) ⁄ )Btk) ⁄ ) BMMC compared with Btk-deficient mice, the production of TNFa, GM-CSF, IL-5 and IL-6 was severely affected in the combined absence of Tec and Btk [37] This indicates that the activity of either Btk or Tec is required for efficient cytokine production One notable exception was IL-4, which was enhanced in Btk-deficient mast cells but severely reduced in Tec) ⁄ ) and in Tec) ⁄ )Btk) ⁄ ) mast cells compared with wild-type cells This indicates differential utilization of Tec and Btk in the regulation of IL-4 production The reason for the differential requirement of Tec and Btk is not known and it remains to be determined whether this is due to transcriptional alterations or post-transcriptional effects, because it has been shown that Btk and Bmx control mRNA stability in human monocytes [48–50] The role of Tec kinases in other mast-cell activation pathways In addition to FceRI stimulation, mast cells can also be activated via other cell-surface receptors such as triggering of TLRs [4,5] TFK have been implicated in TLR signaling in other cell lineages such as monocytes ⁄ macrophages [60], and Btk or Bmx-deficient human monocytes ⁄ macrophages showed, in part, impaired responses upon TLR stimulation [48–50] Because Btk has been shown to interact with components of the TLR2 and TLR4 signaling machinery [83,84], it has been investigated whether the loss of Btk affects TLR signaling in mast cells Activation of Btkdeficient mast cells with various TLR ligands did not impair cytokine production In fact, Btk-deficient cells showed slightly elevated levels of IL-6 and TNFa upon lipopolysaccharide stimulation, indicating a potential negative role in TLR signaling [85] 1996 Another important cell-surface receptor that contributes to the activation of mast cells is c-Kit It has been shown that c-Kit is essential for development, growth and survival of mast cells [86] In addition, c-Kit synergizes with FceRI and c-Kit activation enhances FceRImediated degranulation and cytokine production [87–89] Interestingly, Btk seems to also play an important role in c-Kit signaling Gilfillan and colleagues [69] have observed that the enhancement of mast cell effector functions after c-Kit stimulation was impaired shown in Btk) ⁄ ) BMMCs, indicating that Btk is essential in c-Kit-mediated amplification pathways that enhance FceRI-mediated mast-cell activation Future studies The studies described above clearly indicate that TFK play an important role in the regulation of mast-cell activation The phenotypic analysis of the various Tec kinase-deficient mast cells revealed distinct functions for different members of the Tec kinase family Whereas Btk positively regulates almost any aspect of FceRI-mediated mast cell function (with the exception of IL-4 production which is enhanced in the absence of Btk), the role of Itk and Tec is more specialized and in part also distinct to the role of Btk The observation that Itk-deficient mast cells display enhanced cytokine production indicates a complex utilization of TFK in mast cells Thus, future studies on the role of Tec kinases in mast cells have to address how they are biochemically and molecularly integrated into the various FceRI-induced signaling pathways To the best of our knowledge, there is no study published that investigates Rlk-deficient mast cells Thus, the potential role of Rlk in mast cells should be analyzed Moreover, the comparative analysis of mast cells with combinatorial deletion in Tec kinases (double or triple knockouts) helps us gain a more detailed picture of biochemical and biological functions of TFK in mast cells It will also be important to reconstitute Tec kinase-deficient mast cells with wild-type or kinase-dead version of Tec kinases to determine kinase-independent (i.e scaffolding) functions of Tec family members, because small molecule inhibitors for TFK have been developed [90– 92] Most of the studies on TFK in mast cells have been performed with murine mast cells Because there are species-specific differences between murine and human mast cells [12], it is essential to extend the analysis of TFK to human mast cells Insight from the analysis of human mast cells will indicate whether pharmacological inhibition ⁄ targeting of TFK provides a promising therapeutic strategy for the inhibition of mast-cell activation FEBS Journal 278 (2011) 1990–2000 ª 2011 The Authors Journal compilation ª 2011 FEBS W Ellmeier et al Acknowledgements The authors thank Dr Shinya Sakaguchi for critical reading of the manuscript The work on Tec family kinases in mast cells was supported by the START program (Grant Y-163) of the Austrian Science Fund and the Austrian Ministry of Science and Research, and in part by the FP6 EU Marie Curie RTN ‘Chromatin Plasticity’ References Galli SJ, Tsai M & Piliponsky AM (2008) The development of allergic inflammation Nature 454, 445–454 Stone KD, Prussin C & Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils J Allergy Clin Immunol 125, S73–S80 Marshall JS (2004) Mast-cell responses to pathogens Nat Rev Immunol 4, 787–799 Dawicki W & Marshall JS (2007) New and emerging roles for mast cells in host defence Curr Opin Immunol 19, 31–38 Bischoff SC & Kramer S (2007) Human mast cells, bacteria, and intestinal immunity Immunol Rev 217, 329– 337 Kalesnikoff J & Galli SJ (2008) New developments 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(TFKs) represent another class of protein tyrosine kinases that are implicated in FceRI-mediated mast-cell activation [22] The Tec kinase family. .. production upon FceRI-mediated mast-cell activation Tec is the third member of the Tec kinase family for which a function in mast cells could be identified Studies from our laboratory showed that Tec is... Tec+ ⁄ + and Tec) ⁄ ) BMMC, Tec might specifically contribute to the regulation of LTC4 synthase activity [37] Tec is also required in BMMC for efficient cytokine production In the absence of Tec,