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Volumn 584, Issue 24, 2010, Pages 4933-4940

Mast cell signaling: The role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participants

Author keywords

Fcz RI signal transduction; Fyn; Gab2; Mast cell; Phosphatase; Syk

Indexed keywords

B LYMPHOCYTE RECEPTOR; IMMUNOGLOBULIN E; IMMUNOGLOBULIN E RECEPTOR; IMMUNOGLOBULIN RECEPTOR; PROTEIN GAB2; PROTEIN KINASE; PROTEIN KINASE FYN; PROTEIN KINASE SYK; SMALL INTERFERING RNA; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG;

EID: 78649822101     PISSN: 00145793     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.febslet.2010.08.006     Document Type: Review
Times cited : (125)

References (50)
  • 1
    • 54549103514 scopus 로고    scopus 로고
    • New developments in mast cell biology
    • Kalesnikoff J., Galli S.J. New developments in mast cell biology. Nat. Immunol. 2008, 9:1215-1223.
    • (2008) Nat. Immunol. , vol.9 , pp. 1215-1223
    • Kalesnikoff, J.1    Galli, S.J.2
  • 2
    • 70350356244 scopus 로고    scopus 로고
    • Adapters in the organization of mast cell signaling
    • Alvarez-Errico D., Lessmann E., Rivera J. Adapters in the organization of mast cell signaling. Immunol. Rev. 2009, 232:195-217.
    • (2009) Immunol. Rev. , vol.232 , pp. 195-217
    • Alvarez-Errico, D.1    Lessmann, E.2    Rivera, J.3
  • 4
    • 0242659390 scopus 로고    scopus 로고
    • Mast cell signal transduction from the high-affinity IgE receptor
    • Siraganian R.P. Mast cell signal transduction from the high-affinity IgE receptor. Curr. Opin. Immunol. 2003, 15:639-646.
    • (2003) Curr. Opin. Immunol. , vol.15 , pp. 639-646
    • Siraganian, R.P.1
  • 5
    • 0034634638 scopus 로고    scopus 로고
    • Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody
    • Zhang J., Billingsley M.L., Kincaid R.L., Siraganian R.P. Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody. J. Biol. Chem. 2000, 275:35442-35447.
    • (2000) J. Biol. Chem. , vol.275 , pp. 35442-35447
    • Zhang, J.1    Billingsley, M.L.2    Kincaid, R.L.3    Siraganian, R.P.4
  • 6
    • 0027433055 scopus 로고
    • Protein-tyrosine kinase p72syk in high affinity IgE receptor signaling. Identification as a component of pp72 and association with the receptor gamma chain after receptor aggregation
    • Benhamou M., Ryba N.J., Kihara H., Nishikata H., Siraganian R.P. Protein-tyrosine kinase p72syk in high affinity IgE receptor signaling. Identification as a component of pp72 and association with the receptor gamma chain after receptor aggregation. J. Biol. Chem. 1993, 268:23318-23324.
    • (1993) J. Biol. Chem. , vol.268 , pp. 23318-23324
    • Benhamou, M.1    Ryba, N.J.2    Kihara, H.3    Nishikata, H.4    Siraganian, R.P.5
  • 8
    • 77950377028 scopus 로고    scopus 로고
    • Molecular basis of calcium signaling in lymphocytes: STIM and ORAI
    • Hogan P.G., Lewis R.S., Rao A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 2010, 28:491-533.
    • (2010) Annu. Rev. Immunol. , vol.28 , pp. 491-533
    • Hogan, P.G.1    Lewis, R.S.2    Rao, A.3
  • 9
    • 57849148942 scopus 로고    scopus 로고
    • Calcium signaling in immune cells
    • Vig M., Kinet J.P. Calcium signaling in immune cells. Nat. Immunol. 2009, 10:21-27.
    • (2009) Nat. Immunol. , vol.10 , pp. 21-27
    • Vig, M.1    Kinet, J.P.2
  • 11
    • 0031279370 scopus 로고    scopus 로고
    • Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor
    • Kimura T., Zhang J., Sagawa K., Sakaguchi K., Appella E., Siraganian R.P. Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. J. Immunol. 1997, 159:4426-4434.
    • (1997) J. Immunol. , vol.159 , pp. 4426-4434
    • Kimura, T.1    Zhang, J.2    Sagawa, K.3    Sakaguchi, K.4    Appella, E.5    Siraganian, R.P.6
  • 12
    • 77952887713 scopus 로고    scopus 로고
    • The SYK tyrosine kinase: a crucial player in diverse biological functions
    • Mocsai A., Ruland J., Tybulewicz V.L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 2010, 10:387-402.
    • (2010) Nat. Rev. Immunol. , vol.10 , pp. 387-402
    • Mocsai, A.1    Ruland, J.2    Tybulewicz, V.L.3
  • 13
    • 0036034183 scopus 로고    scopus 로고
    • Protein tyrosine kinase Syk in mast cell signaling
    • Siraganian R.P., Zhang J., Suzuki K., Sada K. Protein tyrosine kinase Syk in mast cell signaling. Mol. Immunol. 2002, 38:1229-1233.
    • (2002) Mol. Immunol. , vol.38 , pp. 1229-1233
    • Siraganian, R.P.1    Zhang, J.2    Suzuki, K.3    Sada, K.4
  • 14
    • 0030018183 scopus 로고    scopus 로고
    • 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
    • Zhang J., Berenstein E.H., Evans R.L., Siraganian R.P. Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells. J. Exp. Med. 1996, 184:71-79.
    • (1996) J. Exp. Med. , vol.184 , pp. 71-79
    • Zhang, J.1    Berenstein, E.H.2    Evans, R.L.3    Siraganian, R.P.4
  • 15
    • 67650370014 scopus 로고    scopus 로고
    • FcεRI-induced activation by low antigen concentrations results in nuclear signals in the absence of degranulation
    • Grodzki A.C., Moon K.D., Berenstein E.H., Siraganian R.P. FcεRI-induced activation by low antigen concentrations results in nuclear signals in the absence of degranulation. Mol. Immunol. 2009, 46:2539-2547.
    • (2009) Mol. Immunol. , vol.46 , pp. 2539-2547
    • Grodzki, A.C.1    Moon, K.D.2    Berenstein, E.H.3    Siraganian, R.P.4
  • 16
    • 77956197813 scopus 로고    scopus 로고
    • Tyrosines in the carboxy-terminus regulate Syk kinase activity and function. J. Biol. Chem. 285, in press
    • de Castro, R.O., Zhang, J., Jamur, M.C., Oliver, C. and Siraganian, R.P. (2010) Tyrosines in the carboxy-terminus regulate Syk kinase activity and function. J. Biol. Chem. 285, in press.
    • (2010)
    • de Castro, R.O.1    Zhang, J.2    Jamur, M.C.3    Oliver, C.4    Siraganian, R.P.5
  • 17
    • 77952406358 scopus 로고    scopus 로고
    • The limited contribution of Fyn and Gab2 to the high affinity IgE receptor signaling in mast cells
    • Barbu E.A., Zhang J., Siraganian R.P. The limited contribution of Fyn and Gab2 to the high affinity IgE receptor signaling in mast cells. J. Biol. Chem. 2010, 285:15761-15768.
    • (2010) J. Biol. Chem. , vol.285 , pp. 15761-15768
    • Barbu, E.A.1    Zhang, J.2    Siraganian, R.P.3
  • 18
    • 0029970787 scopus 로고    scopus 로고
    • Downstream signaling molecules bind to different phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) peptides of the high affinity IgE receptor
    • Kimura T., Kihara H., Bhattacharyya S., Sakamoto H., Appella E., Siraganian R.P. Downstream signaling molecules bind to different phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) peptides of the high affinity IgE receptor. J. Biol. Chem. 1996, 271:27962-27968.
    • (1996) J. Biol. Chem. , vol.271 , pp. 27962-27968
    • Kimura, T.1    Kihara, H.2    Bhattacharyya, S.3    Sakamoto, H.4    Appella, E.5    Siraganian, R.P.6
  • 19
    • 10144236517 scopus 로고    scopus 로고
    • syk. Assessment of binding parameters and real time binding kinetics
    • syk. Assessment of binding parameters and real time binding kinetics. J. Biol. Chem. 1996, 271:25308-25315.
    • (1996) J. Biol. Chem. , vol.271 , pp. 25308-25315
    • Chen, T.1
  • 20
    • 0027998631 scopus 로고
    • Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor
    • Kihara H., Siraganian R.P. Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor. J. Biol. Chem. 1994, 269:22427-22432.
    • (1994) J. Biol. Chem. , vol.269 , pp. 22427-22432
    • Kihara, H.1    Siraganian, R.P.2
  • 21
    • 0029864882 scopus 로고    scopus 로고
    • syk by tyrosine phosphorylation or by binding of phosphorylated immunoreceptor tyrosine-based activation motif peptides
    • syk by tyrosine phosphorylation or by binding of phosphorylated immunoreceptor tyrosine-based activation motif peptides. Mol. Cell. Biol. 1996, 16:1471-1478.
    • (1996) Mol. Cell. Biol. , vol.16 , pp. 1471-1478
    • Kimura, T.1    Sakamoto, H.2    Appella, E.3    Siraganian, R.P.4
  • 22
    • 34249105476 scopus 로고    scopus 로고
    • Structural basis for the inhibition of tyrosine kinase activity of ZAP-70
    • Deindl S., Kadlecek T.A., Brdicka T., Cao X., Weiss A., Kuriyan J. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 2007, 129:735-746.
    • (2007) Cell , vol.129 , pp. 735-746
    • Deindl, S.1    Kadlecek, T.A.2    Brdicka, T.3    Cao, X.4    Weiss, A.5    Kuriyan, J.6
  • 24
    • 38449110993 scopus 로고    scopus 로고
    • Quantitative time-resolved phosphoproteomic analysis of mast cell signaling
    • Cao L., et al. Quantitative time-resolved phosphoproteomic analysis of mast cell signaling. J. Immunol. 2007, 179:5864-5876.
    • (2007) J. Immunol. , vol.179 , pp. 5864-5876
    • Cao, L.1
  • 25
    • 50149105176 scopus 로고    scopus 로고
    • Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling
    • Zhang Y., Oh H., Burton R.A., Burgner J.W., Geahlen R.L., Post C.B. Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling. Proc. Natl Acad. Sci. USA 2008, 105:11760-11765.
    • (2008) Proc. Natl Acad. Sci. USA , vol.105 , pp. 11760-11765
    • Zhang, Y.1    Oh, H.2    Burton, R.A.3    Burgner, J.W.4    Geahlen, R.L.5    Post, C.B.6
  • 26
    • 0036888879 scopus 로고    scopus 로고
    • Phosphorylation of Tyr342 in the linker region of Syk is critical for FcεRI signaling in mast cells
    • Zhang J., Berenstein E., Siraganian R.P. Phosphorylation of Tyr342 in the linker region of Syk is critical for FcεRI signaling in mast cells. Mol. Cell. Biol. 2002, 22:8144-8154.
    • (2002) Mol. Cell. Biol. , vol.22 , pp. 8144-8154
    • Zhang, J.1    Berenstein, E.2    Siraganian, R.P.3
  • 27
    • 0032079343 scopus 로고    scopus 로고
    • A unique insert in the linker domain of Syk is necessary for its function in immunoreceptor signalling
    • Latour S., Zhang J., Siraganian R.P., Veillette A. A unique insert in the linker domain of Syk is necessary for its function in immunoreceptor signalling. EMBO J. 1998, 17:2584-2595.
    • (1998) EMBO J. , vol.17 , pp. 2584-2595
    • Latour, S.1    Zhang, J.2    Siraganian, R.P.3    Veillette, A.4
  • 28
    • 0033976068 scopus 로고    scopus 로고
    • Point mutation of a tyrosine in the linker region of Syk results in a gain of function
    • Sada K., Zhang J., Siraganian R.P. Point mutation of a tyrosine in the linker region of Syk results in a gain of function. J. Immunol. 2000, 164:338-344.
    • (2000) J. Immunol. , vol.164 , pp. 338-344
    • Sada, K.1    Zhang, J.2    Siraganian, R.P.3
  • 29
    • 0037020143 scopus 로고    scopus 로고
    • Activation of Syk tyrosine kinase is required for c-Cbl-mediated ubiquitination of FcεRI and Syk in RBL cells
    • Paolini R., et al. Activation of Syk tyrosine kinase is required for c-Cbl-mediated ubiquitination of FcεRI and Syk in RBL cells. J. Biol. Chem. 2002, 277:36940-36947.
    • (2002) J. Biol. Chem. , vol.277 , pp. 36940-36947
    • Paolini, R.1
  • 30
    • 3242804262 scopus 로고    scopus 로고
    • Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor
    • Zhang J., Chiang Y.J., Hodes R.J., Siraganian R.P. Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor. J. Immunol. 2004, 173:1811-1818.
    • (2004) J. Immunol. , vol.173 , pp. 1811-1818
    • Zhang, J.1    Chiang, Y.J.2    Hodes, R.J.3    Siraganian, R.P.4
  • 31
    • 0032532359 scopus 로고    scopus 로고
    • Mutations in the activation loop tyrosines of protein tyrosine kinase Syk abrogate intracellular signaling but not kinase activity
    • Zhang J., Kimura T., Siraganian R.P. Mutations in the activation loop tyrosines of protein tyrosine kinase Syk abrogate intracellular signaling but not kinase activity. J. Immunol. 1998, 161:4366-4374.
    • (1998) J. Immunol. , vol.161 , pp. 4366-4374
    • Zhang, J.1    Kimura, T.2    Siraganian, R.P.3
  • 32
    • 43249129993 scopus 로고    scopus 로고
    • The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development
    • Kulathu Y., Hobeika E., Turchinovich G., Reth M. The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development. EMBO J. 2008, 27:1333-1344.
    • (2008) EMBO J. , vol.27 , pp. 1333-1344
    • Kulathu, Y.1    Hobeika, E.2    Turchinovich, G.3    Reth, M.4
  • 33
    • 0031092657 scopus 로고    scopus 로고
    • 2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells
    • 2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells. J. Immunol. 1997, 158:2350-2355.
    • (1997) J. Immunol. , vol.158 , pp. 2350-2355
    • Nishizumi, H.1    Yamamoto, T.2
  • 34
    • 28244493479 scopus 로고    scopus 로고
    • Impaired FccεRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn deficiency in mast cells
    • Gomez G., Gonzalez-Espinosa C., Odom S., Baez G., Cid M.E., Ryan J.J., Rivera J. Impaired FcεRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn deficiency in mast cells. J. Immunol. 2005, 175:7602-7610.
    • (2005) J. Immunol. , vol.175 , pp. 7602-7610
    • Gomez, G.1    Gonzalez-Espinosa, C.2    Odom, S.3    Baez, G.4    Cid, M.E.5    Ryan, J.J.6    Rivera, J.7
  • 35
    • 0036347746 scopus 로고    scopus 로고
    • Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation
    • Parravicini V., et al. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat. Immunol. 2002, 3:741-748.
    • (2002) Nat. Immunol. , vol.3 , pp. 741-748
    • Parravicini, V.1
  • 36
    • 0036569710 scopus 로고    scopus 로고
    • The adapter molecule Gab2 regulates FccεRI-mediated signal transduction in mast cells
    • Xie Z.H., Ambudkar I., Siraganian R.P. The adapter molecule Gab2 regulates FccεRI-mediated signal transduction in mast cells. J. Immunol. 2002, 168:4682-4691.
    • (2002) J. Immunol. , vol.168 , pp. 4682-4691
    • Xie, Z.H.1    Ambudkar, I.2    Siraganian, R.P.3
  • 37
    • 0035849822 scopus 로고    scopus 로고
    • Essential role for Gab2 in the allergic response
    • Gu H., et al. Essential role for Gab2 in the allergic response. Nature 2001, 412:186-190.
    • (2001) Nature , vol.412 , pp. 186-190
    • Gu, H.1
  • 38
    • 32044474897 scopus 로고    scopus 로고
    • Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FccεRI
    • Yu M., Lowell C.A., Neel B.G., Gu H. Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FccεRI. J. Immunol. 2006, 176:2421-2429.
    • (2006) J. Immunol. , vol.176 , pp. 2421-2429
    • Yu, M.1    Lowell, C.A.2    Neel, B.G.3    Gu, H.4
  • 39
    • 0022371565 scopus 로고
    • Membrane and cytoskeletal changes associated with IgE-mediated serotonin release from rat basophilic leukemia cells
    • Pfeiffer J.R., Seagrave J.C., Davis B.H., Deanin G.G., Oliver J.M. Membrane and cytoskeletal changes associated with IgE-mediated serotonin release from rat basophilic leukemia cells. J. Cell Biol. 1985, 101:2145-2155.
    • (1985) J. Cell Biol. , vol.101 , pp. 2145-2155
    • Pfeiffer, J.R.1    Seagrave, J.C.2    Davis, B.H.3    Deanin, G.G.4    Oliver, J.M.5
  • 40
    • 0026090189 scopus 로고
    • Regulation of the antigen-induced F-actin response in rat basophilic leukemia cells by protein kinase C
    • Apgar J.R. Regulation of the antigen-induced F-actin response in rat basophilic leukemia cells by protein kinase C. J. Cell Biol. 1991, 112:1157-1163.
    • (1991) J. Cell Biol. , vol.112 , pp. 1157-1163
    • Apgar, J.R.1
  • 41
    • 22244480680 scopus 로고    scopus 로고
    • FczzεRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane
    • Nishida K., et al. FczεRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane. J. Cell Biol. 2005, 170:115-126.
    • (2005) J. Cell Biol. , vol.170 , pp. 115-126
    • Nishida, K.1
  • 42
    • 0025369838 scopus 로고
    • Morphological changes induced by the calcium ionophore A23187 in rat basophilic leukemia (2H3) cells
    • Sahara N., Siraganian R.P., Oliver C. Morphological changes induced by the calcium ionophore A23187 in rat basophilic leukemia (2H3) cells. J. Histochem. Cytochem. 1990, 38:975-983.
    • (1990) J. Histochem. Cytochem. , vol.38 , pp. 975-983
    • Sahara, N.1    Siraganian, R.P.2    Oliver, C.3
  • 43
    • 0031437888 scopus 로고    scopus 로고
    • Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FczεRI signaling
    • Okazaki H., Zhang J., Hamawy M.M., Siraganian R.P. Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FczεRI signaling. J. Biol. Chem. 1997, 272:32443-32447.
    • (1997) J. Biol. Chem. , vol.272 , pp. 32443-32447
    • Okazaki, H.1    Zhang, J.2    Hamawy, M.M.3    Siraganian, R.P.4
  • 44
    • 0025196012 scopus 로고
    • Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release
    • Benhamou M., Gutkind J.S., Robbins K.C., Siraganian R.P. Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release. Proc. Natl Acad. Sci. USA 1990, 87:5327-5330.
    • (1990) Proc. Natl Acad. Sci. USA , vol.87 , pp. 5327-5330
    • Benhamou, M.1    Gutkind, J.S.2    Robbins, K.C.3    Siraganian, R.P.4
  • 45
    • 0026577464 scopus 로고
    • Protein-tyrosine phosphorylation: an essential component of FczzεRI signaling
    • Benhamou M., Siraganian R.P. Protein-tyrosine phosphorylation: an essential component of FczεRI signaling. Immunol. Today 1992, 13:195-197.
    • (1992) Immunol. Today , vol.13 , pp. 195-197
    • Benhamou, M.1    Siraganian, R.P.2
  • 46
    • 77953626408 scopus 로고    scopus 로고
    • Small interfering RNA screen for phosphatases involved in IgE-mediated mast cell degranulation
    • Zhang J., Mendoza M., Guiraldelli M.F., Barbu E.A., Siraganian R.P. Small interfering RNA screen for phosphatases involved in IgE-mediated mast cell degranulation. J. Immunol. 2010, 184:7178-7185.
    • (2010) J. Immunol. , vol.184 , pp. 7178-7185
    • Zhang, J.1    Mendoza, M.2    Guiraldelli, M.F.3    Barbu, E.A.4    Siraganian, R.P.5
  • 47
    • 2942739163 scopus 로고    scopus 로고
    • Dysregulated FczεzεRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells
    • Hernandez-Hansen V., et al. Dysregulated FczεRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells. J. Immunol. 2004, 173:100-112.
    • (2004) J. Immunol. , vol.173 , pp. 100-112
    • Hernandez-Hansen, V.1
  • 49
    • 70350402356 scopus 로고    scopus 로고
    • Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation
    • Kambayashi T., Larosa D.F., Silverman M.A., Koretzky G.A. Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation. Immunol. Rev. 2009, 232:99-114.
    • (2009) Immunol. Rev. , vol.232 , pp. 99-114
    • Kambayashi, T.1    Larosa, D.F.2    Silverman, M.A.3    Koretzky, G.A.4
  • 50
    • 34548717153 scopus 로고    scopus 로고
    • Genetic variation influences FczεRI-induced mast cell activation and allergic responses
    • Yamashita Y., et al. Genetic variation influences FczεRI-induced mast cell activation and allergic responses. J. Immunol. 2007, 179:740-743.
    • (2007) J. Immunol. , vol.179 , pp. 740-743
    • Yamashita, Y.1


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