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1
Kitaura, Jiro, Koichi Asai, Mari Maeda-Yamamoto, Yuko Kawakami, Ushio Kikkawa, and Toshiaki Kawakami. "Akt-Dependent Cytokine Production in Mast Cells." Journal of Experimental Medicine 192, no. 5 (September 5, 2000): 729–40. http://dx.doi.org/10.1084/jem.192.5.729.
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Cross-linking of FcεRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcεRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-α promoters. Transcription from the nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IκB-α, a cytoplasmic protein that binds NF-κB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF-α in FcεRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-κB, NF-AT, and AP-1 that contributes to the production of cytokines.
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Nechushtan, Hovav, Michael Leitges, Cellina Cohen, Gillian Kay, and Ehud Razin. "Inhibition of degranulation and interleukin-6 production in mast cells derived from mice deficient in protein kinase Cβ." Blood 95, no. 5 (March 1, 2000): 1752–57. http://dx.doi.org/10.1182/blood.v95.5.1752.005k18_1752_1757.
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The antigen-mediated activation of mast cells by means of IgE antibodies bound to the cell surface leads to direct interactions between FcɛRI receptor cytoplasmic domains and various intracellular proteins. These interactions initiate diverse signal-transduction pathways, and the activation of these pathways results in the immediate release of proinflammatory agents. A delayed response also occurs and includes the release of various cytokines. It is clear that the activation of kinases is a requirement for the exocytosis observed in mast cells. In addition to the tyrosine phosphorylation of the affected system by soluble tyrosine kinases, activity of protein kinase C (PKC) results in serine or threonine phosphorylation of multiple protein substrates. In this study, we found that mast cells derived from PKCβ-deficient mice produce less interleukin 6 in response to IgE-Ag. The inhibition of exocytosis in the PKCβ-deficient mast cells occurred whether the stimuli were due to the aggregation of the mast cell surface FcɛRI or to the calcium ionophore, ionomycin. However, no significant changes were observed in the proliferative response of the mast cells to interleukin 3 (IL-3) or in their apoptotic rate after IL-3 depletion.
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Tam, See-Ying, Mindy Tsai, Masao Yamaguchi, Koji Yano, Joseph H. Butterfield, and Stephen J. Galli. "Expression of Functional TrkA Receptor Tyrosine Kinase in the HMC-1 Human Mast Cell Line and in Human Mast Cells." Blood 90, no. 5 (September 1, 1997): 1807–20. http://dx.doi.org/10.1182/blood.v90.5.1807.
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Abstract Nerve growth factor (NGF ) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen–activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF ), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.
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Dastych, Jaroslaw, Dennis Taub, Mary C. Hardison, and Dean D. Metcalfe. "Tyrosine kinase-deficient Wvc-kit induces mast cell adhesion and chemotaxis." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1291—C1299. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1291.
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W/Wvmice are deficient in tissue mast cells, and mast cells cultured from these mice do not proliferate in response to the c-kit ligand, stem cell factor (SCF). In this paper, we report that mouse bone marrow cultured mast cells derived from W/Wvmice do adhere to fibronectin in the presence of SCF and exhibit chemotaxis to SCF, and we explore this model for the understanding of c-kit-mediated signaling pathways. Both in vitro and in vivo (in intact cells) phosphorylation experiments demonstrated a low residual level of W/Wvc-kit protein phosphorylation. SCF-induced responses in W/Wvmast cells were abolished by the tyrosine kinase inhibitor herbimycin A and by the phospatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin but were not affected by protein kinase C inhibitors. These observations are consistent with the conclusions that Wvc-kit initiates a signaling process that is PI 3-kinase dependent and that mutated Wvc-kit retains the ability to initiate mast cell adhesion and migration.
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Craig, Andrew W. B., and Peter A. Greer. "Fer Kinase Is Required for Sustained p38 Kinase Activation and Maximal Chemotaxis of Activated Mast Cells." Molecular and Cellular Biology 22, no. 18 (September 15, 2002): 6363–74. http://dx.doi.org/10.1128/mcb.22.18.6363-6374.2002.
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ABSTRACT Mast cells play important roles in inflammation and immunity and express the high-affinity immunoglobulin E receptor (FcεRI) and the receptor protein-tyrosine kinase Kit. Aggregation of FcεRI via antigen binding elicits signals leading to the release of preformed inflammatory mediators as well as de novo-synthesized lipid mediators and cytokines and to elevated cell adhesion and migration. Here, we report that in mouse bone marrow-derived mast cells, Fer kinase is activated downstream of activated FcεRI and activated Kit receptor, and this activation is abolished in cells homozygous for a kinase-inactivating mutation in Fer (fer DR/DR ). Interestingly, the highly related Fps/Fes kinase is also activated upon FcεRI aggregation. This report represents the first description of a common signaling pathway activating Fer and Fps/Fes. While Fer-deficient cells showed similar activation of the Erk mitogen-activated protein (MAP) kinases, p38 MAP kinase activation was less sustained than that in wild-type cells. Although no major defects were observed in degranulation, leukotriene biosynthesis, and cytokine secretion, Fer-deficient cells displayed increased adhesion and decreased motility upon activation of FcεRI and the Kit receptor. The restoration of Fer kinase activity in fer DR/DR mast cells resulted in prolonged p38 kinase activation and increased antigen-mediated cell migration of sensitized mast cells. Thus, Fer is required for maximal p38 kinase activation to promote the chemotaxis of activated mast cells. Further studies with mast cells derived from fps/fes-deficient mice will be required to provide insight into the role of Fps/Fes in mast cell activation.
6
Kawakami, Y., L. Yao, T. Miura, S. Tsukada, O. N. Witte, and T. Kawakami. "Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking." Molecular and Cellular Biology 14, no. 8 (August 1994): 5108–13. http://dx.doi.org/10.1128/mcb.14.8.5108.
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Tyrosine phosphorylation of several cellular proteins is one of the earliest signaling events induced by cross-linking of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells or basophils. Tyrosine kinases activated during this process include the Src family kinases, Lyn, c-Yes, and c-Src, and members of another subfamily, Syk and PTK72 (identical or highly related to Syk). Recently, some of us described two novel tyrosine kinases, Emb and Emt, whose expression was limited to subsets of hematopoietic cells, including mast cells. Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice. Here we report that Fc epsilon RI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrow-derived mast cells. A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking. Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents. Co-immunoprecipitation between Btk and receptor subunit beta or gamma was not detected. The data collectively suggest that Btk is not associated with Fc epsilon but that its activation takes place prior to protein kinase C activation and plays a novel role in the Fc epsilon RI signaling pathway.
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Kawakami, Y., L. Yao, T. Miura, S. Tsukada, O. N. Witte, and T. Kawakami. "Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking." Molecular and Cellular Biology 14, no. 8 (August 1994): 5108–13. http://dx.doi.org/10.1128/mcb.14.8.5108-5113.1994.
Full textAbstract:
Tyrosine phosphorylation of several cellular proteins is one of the earliest signaling events induced by cross-linking of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells or basophils. Tyrosine kinases activated during this process include the Src family kinases, Lyn, c-Yes, and c-Src, and members of another subfamily, Syk and PTK72 (identical or highly related to Syk). Recently, some of us described two novel tyrosine kinases, Emb and Emt, whose expression was limited to subsets of hematopoietic cells, including mast cells. Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice. Here we report that Fc epsilon RI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrow-derived mast cells. A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking. Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents. Co-immunoprecipitation between Btk and receptor subunit beta or gamma was not detected. The data collectively suggest that Btk is not associated with Fc epsilon but that its activation takes place prior to protein kinase C activation and plays a novel role in the Fc epsilon RI signaling pathway.
8
Kinashi, T., JA Escobedo, LT Williams, K. Takatsu, and TA Springer. "Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma 1 pathways." Blood 86, no. 6 (September 15, 1995): 2086–90. http://dx.doi.org/10.1182/blood.v86.6.2086.bloodjournal8662086.
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Receptor tyrosine kinases are known to be important in growth and differentiation. We have recently found that c-kit, the tyrosine kinase receptor for steel factor, also regulates cell-matrix adhesion. Because Steel factor helps regulate cell migration and localization, this may be an important biologic function. Integrin adhesiveness is regulated within minutes by c-kit. The signaling pathways for tyrosine kinase stimulation of integrin adhesiveness and their relation to pathways that regulate growth and differentiation over much longer time periods remain uncharacterized. We have studied the effector pathways by which receptor tyrosine kinases regulate cell-matrix adhesion using wild-type and mutant forms of the platelet-derived growth factor (PDGF) receptor, which is closely related to c-kit. The PDGF receptor expressed in mast cells is as potent as c-kit in stimulating adhesion to fibronectin. We show that induction of adhesion is regulated through two independent pathways of phosphatidylinositol 3 kinase (PI3K) and phospholipase C- gamma 1 (PLC gamma)-protein kinase C by elimination of autophosphorylation sites required for activation of PI3K and PLC gamma or in combination with downregulation of protein kinase C or wortmannin. By contrast, a receptor mutated in both the PI3K and PLC gamma association sites can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growth.
9
Rottapel, R., M. Reedijk, D. E. Williams, S. D. Lyman, D. M. Anderson, T. Pawson, and A. Bernstein. "The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor." Molecular and Cellular Biology 11, no. 6 (June 1991): 3043–51. http://dx.doi.org/10.1128/mcb.11.6.3043.
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The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.
10
Rottapel, R., M. Reedijk, D. E. Williams, S. D. Lyman, D. M. Anderson, T. Pawson, and A. Bernstein. "The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor." Molecular and Cellular Biology 11, no. 6 (June 1991): 3043–51. http://dx.doi.org/10.1128/mcb.11.6.3043-3051.1991.
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The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.
11
Currie, S., E. F. Roberts, S. M. Spaethe, N. W. Roehm, and R. M. Kramer. "Phosphorylation and activation of Ca2+-sensitive cytosolic phospholipase A2 in MCII mast cells mediated by high-affinity Fc receptor for IgE." Biochemical Journal 304, no. 3 (December 15, 1994): 923–28. http://dx.doi.org/10.1042/bj3040923.
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In the present study we examined the activation of Ca(2+)-sensitive cytosolic phospholipase A2 (cPLA2) after aggregation of cell-surface high-affinity Fc receptors for IgE (Fc epsilon RI) on mast cells. MCII mast cells (a factor-dependent bone-marrow-derived murine mast cell line) produce significant amounts of leukotriene C4 (LTC4) (70 ng/10(6) cells) on cross-linking of Fc epsilon RI. Using enzymic and immunochemical analysis we found that cPLA2 is the predominant form of this enzyme in MCII mast cells (0.2 micrograms/mg of total protein) and other forms (i.e. secretory PLA2 or Ca2+ independent cytosolic PLA2) could not be detected. Therefore MCII mast cells represent an excellent cellular model for the study of the biochemical mechanism(s) responsible for Fc epsilon RI-induced activation of cPLA2 and the involvement of cPLA2 in Fc epsilon RI-mediated production of LTC4. After activation of Fc epsilon RI by cross-linking, cPLA2 in MCII mast cells exhibited a decreased electrophoretic mobility and its enzyme activity was increased 3-fold. Treatment with phosphatase reversed both the altered electrophoretic mobility and the enhanced enzyme activity demonstrating that they were the result of Fc epsilon RI-induced phosphorylation. On cross-linking of Fc epsilon RI, cPLA2 was phosphorylated within 30 s and appeared to be an early substrate for Fc epsilon RI-activated protein kinases in MCII mast cells. Tyrosine phosphorylation may be a critical component in this process, as genistein, an inhibitor of protein tyrosine kinases, blocked the activation of cPLA2. Using anti-phosphotyrosine antibodies we observed that the activating phosphorylation was not on tyrosine residues of cPLA2, indicating that tyrosine kinases participate upstream in the signalling cascade that couples Fc epsilon RI to cPLA2. We conclude that in MCII mast cells cPLA2 is activated by kinase-dependent mechanisms and may be responsible for Fc epsilon RI-induced mobilization of arachidonic acid for the generation of LTC4.
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Samayawardhena, Lionel, and Andrew W. B. Craig. "Involvement of Fps/Fes and Fer Kinases in c-Kit Signalling in Mast Cells and Mast Cell Leukemias." Blood 106, no. 11 (November 16, 2005): 3887. http://dx.doi.org/10.1182/blood.v106.11.3887.3887.
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Abstract The c-Kit receptor protein-tyrosine kinase (PTK) is required for mast cell differentiation and function. Signalling by c-Kit normally depends on binding its ligand, Stem Cell Factor (SCF). However, several constitutively activating mutations in c-Kit have been described in myeloid leukemias (including mast cell leukemias (MCLs)) and in solid tumors. The objective of this study is to define the involvement of two non-receptor PTKs called Fps/Fes (hereafter referred to as Fps) and Fer in c-Kit signaling in mast cells and MCLs. Recent studies using transgenic mouse strains bearing kinase-inactivating or null mutations in Fer and Fps have revealed roles in hematopoiesis, and in limiting the innate immune response. Recently, we showed that Fer and Fps are activated downstream of the high affinity IgE receptor, FcεRI, in bone marrow-derived mast cells (BMMCs), and that Fer kinase is required for sustained p38 Mitogen-activated protein kinase (MAPK) activation and chemotaxis upon activation of either FcεRI or c-Kit. In this study, we focus on the roles of Fer and Fps in c-Kit signaling in BMMCs. SCF-induced c-Kit activation led to rapid association of both kinases with c-Kit, and increased tyrosine phosphorylation of Fer and Fps. Interestingly, kinase-dead Fps protein was also phosphorylated upon c-Kit activation, suggesting the involvement of an upstream kinase. Pretreatment of BMMCs with the Src family kinase inhibitor SU6656, caused reduced phosphorylation of Fer and Fps upon SCF treatment. This suggests an involvement of one or more Src family kinases (SFKs) in phosphorylating Fps and Fer upon c-Kit activation. We next examined the potential involvement of the Fyn SFK, since it is known to interact with a juxtamembrane site in activated c-Kit and has been linked to Fer activation in other cell types. SCF treatment of BMMCs from Fyn knock-out mice (fyn-null) revealed normal activation of c-Kit, Erk MAPK, but reduced phosphorylation of Fer kinase. Furthermore, we have observed reduced phosphorylation of Shp2 phosphatase, and the p38 and Jnk MAPKs in Fyn-null BMMCs compared to control. We are currently attempting to restore Fyn expression by retroviral transduction to attempt to rescue these signalling defects, and also evaluate potential requirements for Fyn in chemotaxis and cytokine production. Using MCL cell lines harbouring constitutively actived c-Kit (RBL-2H3 and HMC-1), we have observed that phosphorylation of Fer and Fps kinases are inhibited by treating cells with either a c-Kit inhibitor (SU11652) or SFK inhibitor (SU6656). In conclusion, Fer and Fps kinases participate in c-Kit signaling in normal and leukemic mast cells, and Src family kinases likely contribute to their activation. Using mast cells from Fer/Fps-deficient mice, we will identify their downstream targets and determine if they are required for leukemogenesis by an activated c-Kit transgene.
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Shao, Chen, Bingjie Fu, Ning Ji, Shunli Pan, Xiaoxia Zhao, Zhe Zhang, Yuling Qiu, et al. "Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4092. http://dx.doi.org/10.3390/ijms19124092.
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Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.
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McPherson, Victor A., Stephanie Everingham, Robert Karisch, Julie A. Smith, Christian M. Udell, Jimin Zheng, Zongchao Jia, and Andrew W. B. Craig. "Contributions of F-BAR and SH2 Domains of Fes Protein Tyrosine Kinase for Coupling to the FcεRI Pathway in Mast Cells." Molecular and Cellular Biology 29, no. 2 (November 10, 2008): 389–401. http://dx.doi.org/10.1128/mcb.00904-08.
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ABSTRACT This study investigates the roles of Fer-CIP4 homology (FCH)-Bin/amphiphysin/Rvs (F-BAR) and SH2 domains of Fes protein tyrosine kinase in regulating its activation and signaling downstream of the high-affinity immunoglobulin G (IgE) receptor (FcεRI) in mast cells. Homology modeling of the Fes F-BAR domain revealed conservation of some basic residues implicated in phosphoinositide binding (R113/K114). The Fes F-BAR can bind phosphoinositides and induce tubulation of liposomes in vitro. Mutation of R113/K114 to uncharged residues (RK/QQ) caused a significant reduction in phosphoinositide binding in vitro and a more diffuse cytoplasmic localization in transfected COS-7 cells. RBL-2H3 mast cells expressing full-length Fes carrying the RK/QQ mutation show defects in FcεRI-induced Fes tyrosine phosphorylation and degranulation compared to cells expressing wild-type Fes. This correlated with reduced localization to Lyn kinase-containing membrane fractions for the RK/QQ mutant compared to wild-type Fes in mast cells. The Fes SH2 domain also contributes to Fes signaling in mast cells, via interactions with the phosphorylated FcεRI β chain and the actin regulatory protein HS1. We show that Fes phosphorylates C-terminal tyrosine residues in HS1 implicated in actin stabilization. Thus, coordinated actions of the F-BAR and SH2 domains of Fes allow for coupling to FcεRI signaling and potential regulation the actin reorganization in mast cells.
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de Castro, Rodrigo Orlandini. "Regulation and Function of Syk Tyrosine Kinase in Mast Cell Signaling and Beyond." Journal of Signal Transduction 2011 (May 12, 2011): 1–9. http://dx.doi.org/10.1155/2011/507291.
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The protein tyrosine kinase Syk plays a critical role in FcεRI signaling in mast cells. Binding of Syk to phosphorylated immunoreceptor tyrosine-based activation motifs (p-ITAM) of the receptor subunits results in conformational changes and tyrosine phosphorylation at multiple sites that leads to activation of Syk. The phosphorylated tyrosines throughout the molecule play an important role in the regulation of Syk-mediated signaling. Reconstitution of receptor-mediated signaling in Syk-/- cells by wild-type Syk or mutants which have substitution of these tyrosines with phenylalanine together with in vitro assays has been useful strategies to understand the regulation and function of Syk.
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Kitaura, Jiro, Tatsuya Kinoshita, Masaaki Matsumoto, Shaun Chung, Yuko Kawakami, Michael Leitges, Dianqing Wu, Clifford A. Lowell, and Toshiaki Kawakami. "IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion." Blood 105, no. 8 (April 15, 2005): 3222–29. http://dx.doi.org/10.1182/blood-2004-11-4205.
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AbstractMast cells are the major effector cells for immediate hypersensitivity and chronic allergic reactions. These cells accumulate in mucosal tissues of allergic reactions, where immunoglobulin E (IgE) is produced locally. Here we provide evidence that, in addition to antigen that can attract IgE-bound mast cells, the type of IgE molecules that efficiently activate mast cells can promote the migration of mast cells in the absence of antigen. IgE- and IgE+Ag-mediated migration involves an autocrine/paracrine secretion of soluble factors including adenosine, leukotriene B4, and several chemokines. Their secretion depends on 2 tyrosine kinases, Lyn and Syk, and they are agonists of G-protein-coupled receptors and signal through phosphatidylinositol 3-kinase γ, leading to mast cell migration. In mouse experiments, naive mast cells are attracted to IgE, and IgE-sensitized mast cells are attracted to antigen. Therefore, IgE and antigen are implicated in mast cell accumulation at allergic tissue sites with local high IgE levels. (Blood. 2005;105:3222-3229)
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Simon, Clotilde, Elisabetta Dondi, Amandine Chaix, Paulo de Sepulveda, Terrance J. Kubiseski, Nadine Varin-Blank, and Laura Velazquez. "Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells." Blood 112, no. 10 (November 15, 2008): 4039–47. http://dx.doi.org/10.1182/blood-2008-05-154849.
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Abstract Stem cell factor (SCF) plays critical roles in proliferation, survival, migration, and function of hematopoietic progenitor and mast cells through binding to Kit receptor. Previous studies have implicated the adaptor protein Lnk as an important negative regulator of SCF signaling. However, the molecular mechanism underlying this regulation is unclear. Here, we showed that the Src homology 2 domain (SH2) of Lnk binds directly and preferentially to phosphorylated tyrosine 567 in Kit juxtamembrane domain. Using Lnk−/− bone marrow mast cells (BMMCs) transduced with different Lnk proteins, we demonstrated that Lnk down-regulates SCF-induced proliferation with attenuation of mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase signaling. Furthermore, we showed that Lnk−/− BMMCs displayed increased SCF-dependent migration compared with wild-type cells, revealing a novel Lnk-mediated inhibitory function. This correlated with enhanced Rac and p38 MAPK activation. Finally, we found that Lnk domains and carboxy-terminal tyrosine contribute differently to inhibition of in vitro expansion of hematopoietic progenitors. Altogether, our results demonstrate that Lnk, through its binding to Kit tyrosine 567, negatively modulates specific SCF-dependent signaling pathways involved in the proliferation and migration of primary hematopoietic cells.
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Sommers, Connie L., Ronald L. Rabin, Alexander Grinberg, Henry C. Tsay, Joshua Farber, and Paul E. Love. "A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection." Journal of Experimental Medicine 190, no. 10 (November 15, 1999): 1427–38. http://dx.doi.org/10.1084/jem.190.10.1427.
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Summary Recent data indicate that several members of the Tec family of protein tyrosine kinases function in antigen receptor signal transduction. Txk, a Tec family protein tyrosine kinase, is expressed in both immature and mature T cells and in mast cells. By overexpressing Txk in T cells throughout development, we found that Txk specifically augments the phospholipase C (PLC)-γ1–mediated calcium signal transduction pathway upon T cell antigen receptor (TCR) engagement. Although Txk is structurally different from inducible T cell kinase (Itk), another Tec family member expressed in T cells, expression of the Txk transgene could partially rescue defects in positive selection and signaling in itk−/− mice. Conversely, in the itk+/+ (wild-type) background, overexpression of Txk inhibited positive selection of TCR transgenic thymocytes, presumably due to induction of cell death. These results identify a role for Txk in TCR signal transduction, T cell development, and selection and suggest that the Tec family kinases Itk and Txk perform analogous functions.
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Qu, Xiujuan, Kiyonao Sada, Shinkou Kyo, Koichiro Maeno, S. M. Shahjahan Miah, and Hirohei Yamamura. "Negative regulation of FcϵRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b." Blood 103, no. 5 (March 1, 2004): 1779–86. http://dx.doi.org/10.1182/blood-2003-07-2260.
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AbstractAggregation of the high-affinity immunoglobulin E (IgE) receptor (FcϵRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft after FcϵRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcϵRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcϵRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcϵRI, Syk, phospholipase C-γ (PLC-γ), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor κB kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcϵRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcϵRI-mediated mast cell activation.
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Lorenz, U., A. D. Bergemann, H. N. Steinberg, J. G. Flanagan, X. Li, S. J. Galli, and B. G. Neel. "Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-Kit by the protein tyrosine phosphatase SHP1." Journal of Experimental Medicine 184, no. 3 (September 1, 1996): 1111–26. http://dx.doi.org/10.1084/jem.184.3.1111.
Full textAbstract:
Receptor protein tyrosine kinases (RTKs) transmit downstream signals via interactions with secondary signaling molecules containing SH2 domains. Although many SH2-phosphotyrosyl interactions have been defined in vitro, little is known about the physiological significance of specific RTK/SH2 interactions in vivo. Also, little is known about the mechanisms by which specific RTKs interact with and/or are regulated by specific protein tyrosine phosphatases (PTPs). To address such issue, we carried out a genetic analysis of the previously reported biochemical interaction between the RTK c-Kit, encoded at the W locus, and the SH2-containing non-transmembrane PTP SHP1, encoded at the motheaten (me) locus (1). Mice carrying a kinase-defective allele of c-Kit (Wv/+) were crossed with me/+ mice, which carry one effectively null allele of SHP1, and then backcrossed to generate all possible allelic combinations. Our results indicate strong intergenic complementation between these loci in hematopoietic progenitor cells. Compared to progenitors purified from normal mice, bone marrow progenitor cells (lin-) from me/me mice markedly hyper-proliferated in response to Kit ligand (KL). stimulation. Superimposition of the me/me genotype increased the number of one marrow-derived CFU-E from Wv/+ mice. Conversely, the presence of one or two copies of Wv decreased the number of macrophages and granulocytes in me/me lung, skin, peripheral blood and bone marrow, thereby decreasing the severity of the me/me phenotype. The decrease in dermal mast cells in Wv/Wv mice was rescued to levels found in Wv/+mice by superimposition of the me/me genotype. Surprisingly, however, the presence or absence of SHP1 had no effect on the proliferative response of bone marrow-derived cultured mast cells to KL or IL3 ex vivo. Nevertheless, the immediate-early response to KL stimulation, as measured by KL-induced tyrosyl phosphorylation, was substantially increased in mast cells from Wv/+:me/me compared to Wv/ +:+/+ mice, strongly suggesting that SHP1 directly dephosphorylates and regulates c-Kit. Taken together, our results establish that SHP1 negatively regulates signaling from c-Kit in vivo, but in a cell type-specific manner.
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Kinashi, T., and TA Springer. "Steel factor and c-kit regulate cell-matrix adhesion." Blood 83, no. 4 (February 15, 1994): 1033–38. http://dx.doi.org/10.1182/blood.v83.4.1033.1033.
Full textAbstract:
Abstract Steel (SI) and white spotting (W) loci encode steel factor (c-kit ligand) and the c-kit tyrosine kinase receptor, respectively. Mutations at these loci affect migration and differentiation of primordial germ cells, neural crest-derived melanoblasts, and hematopoietic cells. In these processes, cell adhesion molecules are hypothesized to be crucial. We have examined the role of steel factor and c-kit in cell- extracellular matrix adhesion using bone marrow-derived mast cells as a model system. Steel factor stimulates mast cells to bind to fibronectin and, to a lesser extent, to vitronectin, whereas interleukin-3 and interleukin-4, which are also mast cell growth factors, do not. Activation of adhesiveness is transient, occurs at concentrations of steel factor 100-fold lower than required for growth stimulation, and requires the integrin VLA-5. Mast cells from c-kit mutant mice adhere to fibronectin on stimulation with phorbol 12-myristate 13-acetate (PMA), but not on stimulation with steel factor, indicating that stimulation of integrin adhesiveness requires activation of the c-kit protein tyrosine kinase. By contrast, c-kit mutant and wild-type mast cells adhere equally well to COS cells expressing membrane-anchored steel factor, showing that the kinase activity of c-kit is not required for adhesion directly mediated by c-kit. Our findings suggest that regulation of adhesion is an important biologic function of steel factor.
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Kinashi, T., and TA Springer. "Steel factor and c-kit regulate cell-matrix adhesion." Blood 83, no. 4 (February 15, 1994): 1033–38. http://dx.doi.org/10.1182/blood.v83.4.1033.bloodjournal8341033.
Full textAbstract:
Steel (SI) and white spotting (W) loci encode steel factor (c-kit ligand) and the c-kit tyrosine kinase receptor, respectively. Mutations at these loci affect migration and differentiation of primordial germ cells, neural crest-derived melanoblasts, and hematopoietic cells. In these processes, cell adhesion molecules are hypothesized to be crucial. We have examined the role of steel factor and c-kit in cell- extracellular matrix adhesion using bone marrow-derived mast cells as a model system. Steel factor stimulates mast cells to bind to fibronectin and, to a lesser extent, to vitronectin, whereas interleukin-3 and interleukin-4, which are also mast cell growth factors, do not. Activation of adhesiveness is transient, occurs at concentrations of steel factor 100-fold lower than required for growth stimulation, and requires the integrin VLA-5. Mast cells from c-kit mutant mice adhere to fibronectin on stimulation with phorbol 12-myristate 13-acetate (PMA), but not on stimulation with steel factor, indicating that stimulation of integrin adhesiveness requires activation of the c-kit protein tyrosine kinase. By contrast, c-kit mutant and wild-type mast cells adhere equally well to COS cells expressing membrane-anchored steel factor, showing that the kinase activity of c-kit is not required for adhesion directly mediated by c-kit. Our findings suggest that regulation of adhesion is an important biologic function of steel factor.
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Pan, Jingxuan, Hagop Kantarjian, Jorge Cortes, Francis Giles, and Srdan Verstovsek. "Effect of Tyrosine Kinase Inhibitor INNO-406 on Human Mast Cells Bearing Mutated c-KIT Tyrosine Kinase." Blood 108, no. 11 (November 16, 2006): 4890. http://dx.doi.org/10.1182/blood.v108.11.4890.4890.
Full textAbstract:
Abstract Systemic mastocytosis (SM) is characterized by a clonal accumulation of mast cells (MC) in bone marrow and other tissues. Malignant MC have abnormal spindle shape, express aberrant surface markers, and carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V). This mutation results in a constitutively activated c-kit receptor associated tyrosine kinase and is responsible for disease progression. Agents that affect mutated c-kit may have clinical benefit in SM, but there is none clinically available. INNO-406 is a novel multi-targeted tyrosine kinase inhibitor, previously shown to inhibit the growth of cells expressing c-kit by inhibiting its phosphorylation (Kimura, Blood, 106:3948–54, 2005). We investigated the effects of INNO-406 on mast cells with mutated c-KIT, and compared it to that of imatinib mesylate, tyrosine kinase inhibitor effective against selected c-KIT mutants. HMC-1560 cells carrying juxtamembrane domain c-KIT mutation in codon 560, and HMC-1560, 816 cells carrying both codon 560 mutation and tyrosine kinase domain c-KIT mutation in codon 816, were exposed to increasing concentrations (0.02 to 5 μM) of INNO-406 or imatinib in 72-hour cell proliferation assay. Both INNO-406 and imatinib effectively inhibited the growth of HMC-1560 cells, with IC50 of 45 and 75nM, respectively. Neither drug was effective against HMC-1560, 816 cells at the doses tested. INNO-406 effectively induced apoptosis in HMC-1560, but not in HMC-1560, 816 cells, as judged by the Annexin V flow cytometry test and by PARP specific cleavage seen on western blotting. In addition, INNO-406 was effective in inhibiting phosphorylation of c-kit in HMC-1560 cells in nM range. Our results suggest similar potency of INNO-406 and imatinib in mast cells with mutated codon 560 (found in gastrointestinal stromal tumor), but no activity against cells with mutated codon 816 c-KIT (found in SM).
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Mócsai, Attila, Hong Zhang, Zoltán Jakus, Jiro Kitaura, Toshiaki Kawakami, and Clifford A. Lowell. "G-protein–coupled receptor signaling in Syk-deficient neutrophils and mast cells." Blood 101, no. 10 (May 15, 2003): 4155–63. http://dx.doi.org/10.1182/blood-2002-07-2346.
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Abstract The Syk tyrosine kinase is essential for immunoreceptor and multiple integrin functions as well as being implicated in signaling from G-protein–coupled receptors (GPCR) in cell lines, transfection systems, and pharmacologic studies. In contrast, using Syk-deficient primary cells, we show here that Syk does not play a major functional role in chemoattractant/chemokine signaling in neutrophils and mast cells. syk−/− neutrophils showed normal respiratory burst and degranulation in response to the bacterial peptide formyl-Met-Leu-Phe (fMLP). The migration of neutrophils toward fMLP was similarly not affected by the syk−/−mutation. fMLP initiated normal Ca2+-signal, activation of the extracellular signal-related kinase (ERK) and p38 mitogen–activated protein (MAP) kinase cascades, and polymerization of cellular actin in the absence of Syk.syk−/− and wild-type neutrophils also responded similarly to LTB4, C5a, and the chemokines macrophage inflammatory protein-1 (MIP-1)α or MIP-2, both in functional assays and in intracellular signaling mechanisms. Furthermore, bone marrow–derived syk−/− mast cells showed normal activation of the Akt, ERK, and p38 MAP kinase pathways when stimulated by the GPCR ligand adenosine. We conclude that, in contrast to previous reports, Syk does not play a major role in GPCR signaling.
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Drube, Sebastian, Sylvia Heink, Sabine Walter, Tobias Löhn, Mandy Grusser, Alexander Gerbaulet, Luciana Berod, et al. "The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells." Blood 115, no. 19 (May 13, 2010): 3899–906. http://dx.doi.org/10.1182/blood-2009-10-247411.
Full textAbstract:
Abstract Members of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and murine mast cells. The IL-33R–induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH2-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33–induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitutively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses.
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Kim, J., and HJ Kim. "Treatment of a feline cutaneous mast cell tumour using imatinib mesylate as a neoadjuvant tyrosine kinase inhibitor therapeutic agent." Veterinární Medicína 65, No. 2 (February 28, 2020): 84–88. http://dx.doi.org/10.17221/91/2019-vetmed.
Full textAbstract:
A two-year-old spayed female American shorthair cat presented with a rough, circular, exophytic mass on the genital area. The clinical findings and histopathological examination revealed that the mass contained neoplastic mast cells and, thus, was diagnosed as a mast cell tumour. The anatomical location of the mass was not easily accessible for surgical intervention. We administered a targeted therapy using oral imatinib mesylate for eight weeks to reduce the size of the lesion and to facilitate the successful surgical removal. The tumour mass eventually reduced by 21% and was surgically excised. This is possibly the first study to use imatinib mesylate as a tumour reduction neoadjuvant to therapeutically address a feline cutaneous mast cell tumour located in a surgically inaccessible part of the body.
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Kawakami, Yuko, Jiro Kitaura, Daisuke Hata, Libo Yao, and Toshiaki Kawakami. "Functions of Bruton's tyrosine kinase in mast and B cells." Journal of Leukocyte Biology 65, no. 3 (March 1999): 286–90. http://dx.doi.org/10.1002/jlb.65.3.286.
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Matthews, Sharon A., Enrique Rozengurt, and Doreen Cantrell. "Protein Kinase D." Journal of Experimental Medicine 191, no. 12 (June 12, 2000): 2075–82. http://dx.doi.org/10.1084/jem.191.12.2075.
Full textAbstract:
Protein kinase Cs (PKCs) are activated by antigen receptors in lymphocytes, but little is known about proximal targets for PKCs in antigen receptor–mediated responses. In this report, we define a role for diacylglycerol-regulated PKC isoforms in controlling the activity of the serine/threonine kinase protein kinase D (PKD; also known as PKCμ) in T cells, B cells, and mast cells. Antigen receptor activation of PKD is a rapid and sustained response that can be seen in T cells activated via the T cell antigen receptor, B cells activated via the B cell antigen receptor, and in mast cells triggered via the high-affinity receptor for IgE (FcεR1). Herein, we show that antigen receptor activation of PKD requires the activity of classical/novel PKCs. Moreover, PKC activity is sufficient to bypass the requirement for antigen receptor signals in the induction of PKD activity. These biochemical and genetic studies establish a role for antigen receptor–regulated PKC enzymes in the control of PKD activity. Regulation of PKD activity through upstream PKCs reveals a signaling network that exists between different members of the PKC superfamily of kinases that can operate to amplify and disseminate antigen receptor signals generated at the plasma membrane.
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Klebanovych, Sládková, Sulimenko, Vosecká, Čapek, Dráberová, Dráber, and Sulimenko. "Regulation of Microtubule Nucleation in Mouse Bone Marrow-Derived Mast Cells by Protein Tyrosine Phosphatase SHP-1." Cells 8, no. 4 (April 11, 2019): 345. http://dx.doi.org/10.3390/cells8040345.
Full textAbstract:
The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control their rearrangement are largely unknown. Microtubule nucleation is mediated by γ-tubulin complexes. In this study, we report on the regulation of microtubule nucleation in bone marrow-derived mast cells (BMMCs) by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1; Ptpn6). Reciprocal immunoprecipitation experiments and pull-down assays revealed that SHP-1 is present in complexes containing γ-tubulin complex proteins and protein tyrosine kinase Syk. Microtubule regrowth experiments in cells with deleted SHP-1 showed a stimulation of microtubule nucleation, and phenotypic rescue experiments confirmed that SHP-1 represents a negative regulator of microtubule nucleation in BMMCs. Moreover, the inhibition of the SHP-1 activity by inhibitors TPI-1 and NSC87877 also augmented microtubule nucleation. The regulation was due to changes in γ-tubulin accumulation. Further experiments with antigen-activated cells showed that the deletion of SHP-1 stimulated the generation of microtubule protrusions, the activity of Syk kinase, and degranulation. Our data suggest a novel mechanism for the suppression of microtubule formation in the later stages of mast cell activation.
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Rivera, V. M., and J. S. Brugge. "Clustering of Syk is sufficient to induce tyrosine phosphorylation and release of allergic mediators from rat basophilic leukemia cells." Molecular and Cellular Biology 15, no. 3 (March 1995): 1582–90. http://dx.doi.org/10.1128/mcb.15.3.1582.
Full textAbstract:
In mast cells, antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, stimulates tyrosine phosphorylation and activation of multiple signaling pathways leading to the release of several classes of mediators of the allergic response. Early events induced upon cross-linking of Fc epsilon RI include tyrosine phosphorylation of Fc epsilon RI subunits and activation of the tyrosine kinase p72syk (Syk), which binds to tyrosine-phosphorylated Fc epsilon RI. Clustering of Syk, as a result of its interaction with aggregated Fc epsilon RI, may play a role in activating one or more of the signaling pathways leading to mediator release. To test this possibility, Syk was introduced into a model mast cell line (rat basophilic leukemia cells) as part of a chimeric transmembrane protein containing the extracellular and transmembrane domains of CD16 and CD7, respectively. Clustering of the Syk chimera, using antibodies against CD16, was found to be sufficient to stimulate early and late events normally induced by clustering of Fc epsilon RI. Specifically, aggregation of Syk induced degranulation, leukotriene synthesis, and expression of cytokine genes. Induction of mediator release was dependent on the kinase activity of Syk. Consistent with this finding, clustering of Syk also induced the tyrosine phosphorylation of a profile of proteins, including phospholipase C-gamma 1 and mitogen-activated protein kinase, similar to that induced upon clustering of Fc epsilon RI. These results strongly suggest that Syk is an early and critical mediator of multiple signaling pathways that emanate from the Fc epsilon RI receptor and give rise to the allergic response.
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Verstovsek, Srdan, Cem Akin, Giles J. Francis, Manshouri Taghi, Ly Huynh, Paul W. Manley, Leila Alland, Margaret Dugan, Jorge E. Cortes, and Kantarjian M. Hagop. "Effects of AMN107, a Novel Aminopyrimidine Tyrosine Kinase Inhibitor, on Human Mast Cells Bearing Wild-Type or Mutated Codon 816 c-kit." Blood 106, no. 11 (November 16, 2005): 3528. http://dx.doi.org/10.1182/blood.v106.11.3528.3528.
Full textAbstract:
Abstract Background. Majority of adult patients with systemic mastocytosis (SM) have activating mutation in codon 816 of c-kit (CD117), a receptor on the surface of mast cells. This abnormality is responsible for the pathogenesis of the disease. Methods. We investigated the effects of a newly designed tyrosine kinase inhibitor, AMN107, by comparing its in vitro inhibitory potency on c-kit mutated mast cell lines and patient samples with that of imatinib mesylate, another tyrosine kinase inhibitor, effective in some patients with SM. Two cell lines, subclones of HMC-1 cells, were used: HMC-1560 carrying juxtamembrane domain mutation in codon 560 of c-kit, and HMC-1560, 816 carrying both codon 560 mutation and tyrosine kinase domain mutation in codon 816 of c-kit. Results. In HMC-1560 mast cell line carrying wild-type codon 816, AMN107 was as potent as imatinib in inhibiting cellular proliferation, with IC50 values of 108 and 74 nM respectively, while in HMC-1560, 816 cell line carrying 816 mutation, neither medication had an effect. AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit tyrosine kinase in HMC-1560 cells. The inhibition of cellular proliferation was associated with induction of apoptosis in HMC-1560 cells. AMN107 in concentrations up to 1 uM had no effect on bone marrow mast cells carrying D816V c-kit mutation obtained from patients with mastocytosis. Conclusions. Our results suggest similar potency of AMN107 and imatinib in mast cells that carry wild-type codon 816, but no activity against codon 816 mutation carrying cells.
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Fumo, Gerard, Cem Akin, Dean D. Metcalfe, and Len Neckers. "17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells." Blood 103, no. 3 (February 1, 2004): 1078–84. http://dx.doi.org/10.1182/blood-2003-07-2477.
Full textAbstract:
AbstractMutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer. (Blood. 2004;103:1078-1084)
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Manetz, Timothy Scott, Claudia Gonzalez-Espinosa, Ramachandran Arudchandran, Sandhya Xirasagar, Victor Tybulewicz, and Juan Rivera. "Vav1 Regulates Phospholipase Cγ Activation and Calcium Responses in Mast Cells." Molecular and Cellular Biology 21, no. 11 (June 1, 2001): 3763–74. http://dx.doi.org/10.1128/mcb.21.11.3763-3774.2001.
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ABSTRACT The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcɛRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1-deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcɛRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase Cγ1 (PLCγ1) and PLCγ2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLCγ1 and PLCγ2 and calcium responses. Thus, Vav1 is essential to FcɛRI-mediated activation of PLCγ and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLCγ-activated calcium signals.
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Heinrich, Michael C., Diana J. Griffith, Brian J. Druker, Cecily L. Wait, Kristen A. Ott, and Amy J. Zigler. "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor." Blood 96, no. 3 (August 1, 2000): 925–32. http://dx.doi.org/10.1182/blood.v96.3.925.
Full textAbstract:
Abstract STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
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Heinrich, Michael C., Diana J. Griffith, Brian J. Druker, Cecily L. Wait, Kristen A. Ott, and Amy J. Zigler. "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor." Blood 96, no. 3 (August 1, 2000): 925–32. http://dx.doi.org/10.1182/blood.v96.3.925.015k50_925_932.
Full textAbstract:
STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
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Urtz, Nicole, Ana Olivera, Elisa Bofill-Cardona, Robert Csonga, Andreas Billich, Diana Mechtcheriakova, Frederic Bornancin, Max Woisetschläger, Juan Rivera, and Thomas Baumruker. "Early Activation of Sphingosine Kinase in Mast Cells and Recruitment to FcεRI Are Mediated by Its Interaction with Lyn Kinase." Molecular and Cellular Biology 24, no. 19 (October 1, 2004): 8765–77. http://dx.doi.org/10.1128/mcb.24.19.8765-8777.2004.
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ABSTRACT Sphingosine kinase has been recognized as an essential signaling molecule that mediates the intracellular conversion of sphingosine to sphingosine-1-phosphate. In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca2+, released from internal stores, and to degranulation. These events either precede or are concomitant with the activation of phospholipase C-γ and the generation of inositol trisphosphate. Here we show that sphingosine kinase type 1 (SPHK1) interacts directly with the tyrosine kinase Lyn and that this interaction leads to the recruitment of this lipid kinase to the high-affinity receptor for immunoglobulin E (FcεRI). The interaction of SPHK1 with Lyn caused enhanced lipid and tyrosine kinase activity. After FcεRI triggering, enhanced sphingosine kinase activity was associated with FcεRI in sphingolipid-enriched rafts of mast cells. Bone marrow-derived mast cells from Lyn−/ − mice, compared to syngeneic wild-type cells, were defective in the initial induction of SPHK1 activity, and the defect was overcome by retroviral Lyn expression. These findings position the activation of SPHK1 as an FcεRI proximal event.
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Hata, Daisuke, Yuko Kawakami, Naoki Inagaki, Chris S. Lantz, Toshio Kitamura, Wasif N. Khan, Mari Maeda-Yamamoto, et al. "Involvement of Bruton's Tyrosine Kinase in FcεRI-dependent Mast Cell Degranulation and Cytokine Production." Journal of Experimental Medicine 187, no. 8 (April 20, 1998): 1235–47. http://dx.doi.org/10.1084/jem.187.8.1235.
Full textAbstract:
We investigated the role of Bruton's tyrosine kinase (Btk) in FcεRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcεRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcεRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcεRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcεRI signal transduction in mast cells.
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Zhang, J., E. H. Berenstein, R. L. Evans, and R. P. Siraganian. "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." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 71–79. http://dx.doi.org/10.1084/jem.184.1.71.
Full textAbstract:
Aggregation of the high affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells results in rapid tyrosine phosphorylation and activation of Syk, a cytoplasmic protein tyrosine kinase. To examine the role of Syk in the Fc epsilon RI signaling pathway, we identified a variant of RBL-2H3 cells that has no detectable Syk by immunoblotting and by in vitro kinase reactions. In these Syk-deficient TB1A2 cells, aggregation of Fc epsilon RI induced no histamine release and no detectable increase in total cellular protein tyrosine phosphorylation. However, stimulation of these cells with the calcium ionophore did induce degranulation. Fc epsilon RI aggregation induced tyrosine phosphorylation of the beta and gamma subunits of the receptor, but no increase in the tyrosine phosphorylation of phospholipase C-gamma 1 and phospholipase C-gamma 2 and no detectable increase in intracellular free Ca2+ concentration. By transfection, cloned lines were established with stable expression of Syk. In these reconstituted cells, Fc epsilon RI aggregation induced tyrosine phosphorylation of phospholipase C-gamma 1 and phospholipase C-gamma 2, an increase in intracellular free Ca2+ and histamine release. These results demonstrate that Syk plays a critical role in the early Fc epsilon RI-mediated signaling events. It further demonstrates that Syk activation occurs downstream of receptor phosphorylation, but upstream of most of the Fc epsilon RI-mediated protein tyrosine phosphorylations.
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Taylor, Marcia L., Jaroslaw Dastych, Devinder Sehgal, Magnus Sundstrom, Gunnar Nilsson, Cem Akin, Rose G. Mage, and Dean D. Metcalfe. "The Kit-activating mutation D816V enhances stem cell factor–dependent chemotaxis." Blood 98, no. 4 (August 15, 2001): 1195–99. http://dx.doi.org/10.1182/blood.v98.4.1195.
Full textAbstract:
The D816V mutation of c-kit has been detected in patients with mastocytosis. This mutation leads to constitutive tyrosine kinase activation of Kit. Because stem cell factor (SCF), the ligand for Kit (CD117+), is a chemoattractant for CD117+ cells and one feature of mastocytosis is an abnormal collection of mast cells in tissues derived from CD34+CD117+ mast cell precursors, the hypothesis was considered that the D816V mutation would enhance chemotaxis of these precursor cells. Constructs encoding wild-type Kit or Kit bearing the D816V mutation were transfected into Jurkat cells, labeled with Calcein-am, and migration to SCF assessed in the presence or absence of tyrosine kinase inhibitors. Chemotaxis to SCF was enhanced in D816V transfectants compared to wild-type Kit transfectants (P < .002). Migration of both transfectants was inhibited by tyrosine kinase inhibitors, although D816V transfectants were more sensitive. Chemotaxis was next performed on CD34+CD117+ circulating mast cell precursors obtained from patients with mastocytosis. Analysis of prechemotaxis and migrated cells showed that whereas less than 10% in the prechemotaxis sample had the D816V mutation, 40% to 80% of migrated cells had this mutation. These results demonstrate that the D816V Kit mutation enhances chemotaxis of CD117+ cells, offering one explanation for increased mast cells observed in tissues of patients with mastocytosis.
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Volná, Petra, Pavel Lebduška, Lubica Dráberová, Šárka Šímová, Petr Heneberg, Michael Boubelík, Viktor Bugajev, et al. "Negative Regulation of Mast Cell Signaling and Function by the Adaptor LAB/NTAL." Journal of Experimental Medicine 200, no. 8 (October 11, 2004): 1001–14. http://dx.doi.org/10.1084/jem.20041213.
Full textAbstract:
Engagement of the Fcε receptor I (FcεRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non–T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow–derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcεRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C γ1 and phospholipase C γ2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca2+. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain–containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.
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Barker, S. A., K. K. Caldwell, A. Hall, A. M. Martinez, J. R. Pfeiffer, J. M. Oliver, and B. S. Wilson. "Wortmannin blocks lipid and protein kinase activities associated with PI 3-kinase and inhibits a subset of responses induced by Fc epsilon R1 cross-linking." Molecular Biology of the Cell 6, no. 9 (September 1995): 1145–58. http://dx.doi.org/10.1091/mbc.6.9.1145.
Full textAbstract:
We have investigated the effects of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), on antigen-mediated signaling in the RBL-2H3 mast cell model. In RBL-2H3 cells, the cross-linking of high affinity IgE receptors (Fc epsilon R1) activates at least two cytoplasmic protein tyrosine kinases, Lyn and Syk, and stimulates secretion, membrane ruffling, spreading, pinocytosis, and the formation of actin plaques implicated in increased cell-substrate adhesion. In addition, Fc epsilon R1 cross-linking activates PI 3-kinase. It was previously shown that wortmannin causes a dose-dependent inhibition of PI 3-kinase activity and also inhibits antigen-stimulated degranulation. We report that the antigen-induced synthesis of inositol(1,4,5)P3 is also markedly inhibited by wortmannin. Consistent with evidence in other cell systems implicating phosphatidylinositol(3,4,5)P3 in ruffling, pretreatment of RBL-2H3 cells with wortmannin inhibits membrane ruffling and fluid pinocytosis in response to Fc epsilon R1 cross-linking. However, wortmannin does not inhibit antigen-induced actin polymerization, receptor internalization, or the actin-dependent processes of spreading and adhesion plaque formation that follow antigen stimulation in adherent cells. Wortmannin also fails to inhibit either of the Fc epsilon R1-coupled tyrosine kinases, Lyn or Syk, or the activation of mitogen-activated protein kinase as measured by in vitro kinase assays. Strikingly, there is substantial in vitro serine/threonine kinase activity in immunoprecipitates prepared from Fc epsilon R1-activated cells using antisera to the p85 subunit of PI 3-kinase. This activity is inhibited by pretreatment of the cells with wortmannin or by the direct addition of wortmannin to the kinase assay, suggesting that PI 3-kinase itself is capable of acting as a protein kinase. We conclude that Fc epsilon R1 cross-linking activates both lipid and protein kinase activities of PI 3-kinase and that inhibiting these activities with wortmannin results in the selective block of a subset of Fc epsilon R1-mediated signaling responses.
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Meininger, CJ, H. Yano, R. Rottapel, A. Bernstein, KM Zsebo, and BR Zetter. "The c-kit receptor ligand functions as a mast cell chemoattractant." Blood 79, no. 4 (February 15, 1992): 958–63. http://dx.doi.org/10.1182/blood.v79.4.958.958.
Full textAbstract:
Abstract Mast cells accumulate at sites of neovascularization, solid tumors, and many immune reactions. Such accumulation requires directed migration of mature mast cells or their precursors. The nature of the chemoattractants that regulate mast cell motility and the identity of the receptors that mediate the chemotactic response are poorly understood. We have tested the ability of stem cell factor (SCF), a mast cell growth factor, to stimulate mast cell migration. Our results show that SCF is a potent mast cell attractant that stimulates directional motility of both mucosal and connective tissue-type mast cells. The activity is potentiated by costimulation with interleukin-3 (IL-3), another mast cell chemoattractant. SCF, a known ligand for the c-kit tyrosine kinase receptor, was unable to stimulate motility in W42 mutant mast cells, which have a defective c-kit tyrosine kinase. However, W42 mast cells were still able to migrate in response to IL-3. These results show that SCF is a chemotactic factor as well as a growth factor and that the c-kit receptor can transduce signals leading to both cell proliferation and increased directional cell motility.
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Meininger, CJ, H. Yano, R. Rottapel, A. Bernstein, KM Zsebo, and BR Zetter. "The c-kit receptor ligand functions as a mast cell chemoattractant." Blood 79, no. 4 (February 15, 1992): 958–63. http://dx.doi.org/10.1182/blood.v79.4.958.bloodjournal794958.
Full textAbstract:
Mast cells accumulate at sites of neovascularization, solid tumors, and many immune reactions. Such accumulation requires directed migration of mature mast cells or their precursors. The nature of the chemoattractants that regulate mast cell motility and the identity of the receptors that mediate the chemotactic response are poorly understood. We have tested the ability of stem cell factor (SCF), a mast cell growth factor, to stimulate mast cell migration. Our results show that SCF is a potent mast cell attractant that stimulates directional motility of both mucosal and connective tissue-type mast cells. The activity is potentiated by costimulation with interleukin-3 (IL-3), another mast cell chemoattractant. SCF, a known ligand for the c-kit tyrosine kinase receptor, was unable to stimulate motility in W42 mutant mast cells, which have a defective c-kit tyrosine kinase. However, W42 mast cells were still able to migrate in response to IL-3. These results show that SCF is a chemotactic factor as well as a growth factor and that the c-kit receptor can transduce signals leading to both cell proliferation and increased directional cell motility.
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Kawakami, Yuko, Libo Yao, Wei Han, and Toshiaki Kawakami. "Tec family protein-tyrosine kinases and pleckstrin homology domains in mast cells." Immunology Letters 54, no. 2-3 (December 1996): 113–17. http://dx.doi.org/10.1016/s0165-2478(96)02659-4.
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Hata, Daisuke, Jiro Kitaura, Stephen E. Hartman, Yuko Kawakami, Takashi Yokota, and Toshiaki Kawakami. "Bruton’s Tyrosine Kinase-mediated Interleukin-2 Gene Activation in Mast Cells." Journal of Biological Chemistry 273, no. 18 (May 1, 1998): 10979–87. http://dx.doi.org/10.1074/jbc.273.18.10979.
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Sasaki, Takehiko, Teiji Wada, Hiroyuki Kishimoto, Junko Irie-Sasaki, Goichi Matsumoto, Takayuki Goto, Zhengbin Yao, et al. "The Stress Kinase Mitogen-Activated Protein Kinase Kinase (Mkk)7 Is a Negative Regulator of Antigen Receptor and Growth Factor Receptor–Induced Proliferation in Hematopoietic Cells." Journal of Experimental Medicine 194, no. 6 (September 17, 2001): 757–68. http://dx.doi.org/10.1084/jem.194.6.757.
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The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stress kinases stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cells. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferation in response to growth factor and antigen receptor stimulation and increased thymic cellularity. Mutation of mkk7 in mast cells resulted in hyperproliferation in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7−/− mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extracellular signal–regulated kinase (ERK)1/2 or p38 MAPK. mkk7−/− mast cells display reduced expression of JunB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7−/− mast cells abrogates the hyperproliferative response. Apoptotic responses to a variety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 negatively regulates growth factor and antigen receptor–driven proliferation in hematopoietic cells. These results indicate that the MKK7-regulated stress signaling pathway can function as negative regulator of cell growth in multiple hematopoietic lineages.
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Metcalfe, Dean D. "Mast cells and mastocytosis." Blood 112, no. 4 (August 15, 2008): 946–56. http://dx.doi.org/10.1182/blood-2007-11-078097.
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Abstract Mast cells have been recognized for well over 100 years. With time, human mast cells have been documented to originate from CD34+ cells, and have been implicated in host responses in both innate and acquired immunity. In clinical immunology, they are recognized for their central role in IgE-mediated degranulation and allergic inflammation by virtue of their expression of the high-affinity receptor for IgE and release of potent proinflammatory mediators. In hematology, the clinical disease of mastocytosis is characterized by a pathologic increase of mast cells in tissues, often associated with mutations in KIT, the receptor for stem cell factor. More recently, and with increased understanding of how human mast cells are activated through receptors including the high-affinity receptor for IgE and KIT, specific tyrosine kinase inhibitors have been identified with the potential to interrupt signaling pathways and thus limit the proliferation of mast cells as well as their activation through immunoglobulin receptors.
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Sada, Kiyonao, S. M. Shahjahan Miah, Koichiro Maeno, Shinkou Kyo, Xiujuan Qu, and Hirohei Yamamura. "Regulation of FcεRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells." Blood 100, no. 6 (September 15, 2002): 2138–44. http://dx.doi.org/10.1182/blood-2001-12-0340.
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Abstract Aggregation of high-affinity IgE receptor FcεRI induces sequential activation of nonreceptor-type protein-tyrosine kinases and subsequent tyrosine phosphorylation of cellular proteins, leading to degranulation in mast cells. A hematopoietic cell–specific adaptor protein, 3BP2, that was originally identified as an Abl SH3-binding protein was rapidly tyrosine phosphorylated by the aggregation of FcεRI on rat basophilic leukemia RBL-2H3 cells. Tyrosine phosphorylation of 3BP2 did not depend on calcium influx from external sources. To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells. Overexpression of 3BP2-SH2 domain resulted in a suppression of antigen-induced degranulation as assessed by β-hexosaminidase release. Even though overall tyrosine phosphorylation of cellular protein was not altered, antigen-mediated tyrosine phosphorylation of phospholipase C-γ (PLC-γ) and calcium mobilization were significantly suppressed in the cells overexpressing the 3BP2-SH2 domain. Furthermore, antigen stimulation induced the association of 3BP2-SH2 domain with LAT and other signaling molecule complexes in the RBL-2H3 cells. FcεRI-mediated phosphorylation of JNK and ERK was not affected by the overexpression of 3BP2-SH2 domain. These data indicate that 3BP2 functions to positively regulate the FcεRI-mediated tyrosine phosphorylation of PLC-γ and thereby the signals leading to degranulation.
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Sawada, Junko, Atsuko Itakura, Akane Tanaka, Tohru Furusaka, and Hiroshi Matsuda. "Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways." Blood 95, no. 6 (March 15, 2000): 2052–58. http://dx.doi.org/10.1182/blood.v95.6.2052.
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Abstract Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. We investigated whether NGF was able to induce directional migration of rat peritoneal mast cells (PMCs). NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinumC2 toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role in mast cell accumulation in allergic and nonallergic inflammatory conditions.
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Stassen, Michael, Christian Müller, Christoph Richter, Christine Neudörfl, Lothar Hültner, Sucharit Bhakdi, Iwan Walev, and Edgar Schmitt. "The Streptococcal Exotoxin Streptolysin O Activates Mast Cells To Produce Tumor Necrosis Factor Alpha by p38 Mitogen-Activated Protein Kinase- and Protein Kinase C-Dependent Pathways." Infection and Immunity 71, no. 11 (November 2003): 6171–77. http://dx.doi.org/10.1128/iai.71.11.6171-6177.2003.
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ABSTRACT Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-α). Mast cell-derived TNF-α plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF-α peaked ∼4 h after stimulation with SLO. Production of TNF-α was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-α. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-α. However, hyperstimulation of mast cells might also lead to overproduction of TNF-α, which would then promote the development of toxic streptococcal syndromes.