The SYK tyrosine kinase: A crucial player in diverse biological functions

Nature Reviews Immunology

Volumn 10, Issue 6, 2010, Pages 387-402

  Mócsai, Attila ^a   Ruland, Jürgen ^b,c   Tybulewicz, Victor L J ^d  

^a SEMMELWEIS UNIVERSITY OF MEDICINE   (Hungary)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c INSTITUTE OF EPIDEMIOLOGY   (Germany)

^d NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNORECEPTOR TYROSINE BASED ACTIVATION MOTIF; INTEGRIN; LECTIN; PROTEIN KINASE SYK; PROTEIN KINASE SYK INHIBITOR; PROTEIN KINASE ZAP 70; TYROSINE DERIVATIVE; UNCLASSIFIED DRUG;

ALLERGY; ANGIOGENESIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B LYMPHOCYTE; BONE METABOLISM; CELL ADHESION; CYTOTOXICITY; DROSOPHILA MELANOGASTER; ENZYME ACTIVATION; ENZYME STRUCTURE; HUMAN; IMMUNE FUNCTION TEST; LEUKOCYTE FUNCTION; MICROORGANISM DETECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; THROMBOCYTE FUNCTION; TISSUE INJURY; TUMOR; VIRUS ONCOGENE;

ANIMALS; CELL ADHESION; CELL LINEAGE; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; PROTEIN-TYROSINE KINASES; RECEPTORS, IMMUNOLOGIC; SIGNAL TRANSDUCTION;

EID: 77952887713     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2765     Document Type: Review

References (190)

1. Reth, M. Antigen receptor tail clue. Nature 338, 383-384 (1989).
2. Poole, A. et al. The Fc receptor y-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J. 16, 2333-2341 (1997).
3. Abtahian, F. et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299, 247-251 (2003).
4. Ziegenfuss, J. S. et al. Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature 453, 935-939 (2008).
5. Mócsai, A. et al. The immunomodulatory adapter proteins DAP12 and Fc receptor y-chain (FcRy) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc. Natl Acad. Sci. USA 101, 6158-6163 (2004).
6. Jakus, Z., Fodor, S., Abram, C. L, Lowell, C. A. & Mócsai, A. Immunoreceptor-like signaling by (32 and (33 integrins. Trends Cell Biol. 17, 493-501 (2007).
7. Kerrigan, A. M. & Brown, G. D. Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs. Immunol. Rev. 234, 335-352 (2010).
8. Pao, L. I., Bedzyk, W. D., Persin, C. & Cambier, J. C. Molecular targets of CD45 in B cell antigen receptor signal transduction. J. Immunol. 158, 1116-1124 (1997).
9. Turner, M., Schweighoffer, E., Colucci, F, Di Santo, J. P. & Tybulewicz, V. L. Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunol. Today 21, 148-154 (2000).
10. Iwaki, S., Jensen, B. M. & Gilfillan, A. M. NTAL/LAB/LAT2. Int. J. Biochem. Cell Biol. 39, 868-873 (2007).
11. Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651-656 (2006).
12. Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-KB activation. Nature Immunol. 3, 836-843 (2002).
13. Hara, H. et al. The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 18, 763-775 (2003).
14. Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-KB activation. Nature Immunol. 3, 830-835 (2002).
15. Ruefli-Brasse, A. A., French, D. M. & Dixit, V. M. Regulation of NF-icB-dependent lymphocyte activation and development by paracaspase. Science 302, 1581-1584 (2003).
16. Gross, O. et al. Multiple ITAM-coupled NK-cell receptors engage the Bcl 10/Malt 1 complex via Carma 1 for NF-KB and MAPK activation to selectively control cytokine production. Blood 112, 2421-2428 (2008).
17. Klemm, S. et al. The Bcl10-Malt1 complex segregates FceRI-mediated nuclear factor KB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337-347 (2006).
18. Hara, H. & Saito, T. CARD9 versus CARMA 1 in innate and adaptive immunity. Trends Immunol. 30, 234-242 (2009).
19. Veillette, A., Latour, S. & Davidson, D. Negative regulation of immunoreceptor signaling. Annu. Rev. Immunol. 20, 669-707 (2002).
20. Lupher, M. L, Jr et al. Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323. J. Biol. Chem. 273, 35273-35281 (1998).
21. Yankee, T M., Keshvara, L. M., Sawasdikosol, S., Harrison, M. L. & Geahlen, R. L. Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain. J. Immunol. 163, 5827-5835 (1999).
22. Rao, N., Dodge, I. & Band, H. The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system. J. Leukoc. Biol. 71, 753-763 (2002).
23. Turner, M. et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378, 298-302 (1995).
24. Cheng, A. M. et al. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 378, 303-306 (1995).
25. Chan, A. C. et al. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency Science 264, 1599-1601 (1994).
26. Elder, M. E. et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264, 1596-1599 (1994).
27. Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435-438 (1995).
28. Henderson, R. B. et al. A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival. J. Exp. Med. 207, 837-853 (2010).
29. Schweighoffer, E., Vanes, L, Mathiot, A., Nakamura, T & Tybulewicz, V. L. Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 18, 523-533 (2003).
30. Palacios, E. H. & Weiss, A. Distinct roles for Syk and ZAP-70 during early thymocyte development. J. Exp. Med. 204, 1703-1715 (2007).
31. Costello, P. S. et al. Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells. Oncogene 13, 2595-2605 (1996).
32. Crowley, M. T et al. A critical role for Syk in signal transduction and phagocytosis mediated by Fcy receptors on macrophages. J. Exp. Med. 186, 1027-1039 (1997).
33. Kiefer, F et al. The Syk protein tyrosine kinase is essential for Fcy receptor signaling in macrophages and neutrophils. Mol. Cell. Biol. 18, 4209-4220 (1998).
34. Colucci, F et al. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nature Immunol. 3, 288-294 (2002).
35. Kane, L. P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242-249 (2000).
36. Au-Yeung, B. B. et al. The structure, regulation, and function of ZAP-70. Immunol. Rev. 228, 41-57 (2009).
37. Daeron, M. Fc receptor biology. Annu. Rev. Immunol. 15, 203-234 (1997).
38. Siraganian, R. P., Zhang, J., Suzuki, K. & Sada, K. Protein tyrosine kinase Syk in mast cell signaling. Mol. Immunol. 38, 1229-1233 (2002).
39. Kraus, M., Alimzhanov, M. B., Rajewsky, N. & Rajewsky, K. Survival of resting mature B lymphocytes depends on BCR signaling via the Iga/(3 heterodimer. Cell 11 7, 787-800 (2004).
40. Kitaura, J. et al. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FceRI. Proc. Natl Acad. Sci. USA 100, 12911-12916 (2003).
41. Kohno, M., Yamasaki, S., Tybulewicz, V. L. & Saito, T Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen. Blood 105, 2059-2065 (2005).
42. Suzuki-Inoue, K. et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 107, 542-549 (2006).
43. Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507-517 (2005).
44. Fuller, G. L. et al. The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. J. Biol. Chem. 282, 12397-12409 (2007).
45. Hughes, C. E. et al. CLEC-2 activates Syk through dimerization. Blood 115, 2947-2955 (2010).
46. Geijtenbeek, T B. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nature Rev. Immunol. 9, 465-479 (2009).
47. Tsang, E. et al. Molecular mechanism of the Syk activation switch. J. Biol. Chem. 283, 32650-32659 (2008).
48. Deindl, S. et al. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129, 735-746 (2007).
49. Deindl, S., Kadlecek, T. A., Cao, X., Kuriyan, J. & Weiss, A. Stability of an auto inhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response. Proc. Natl Acad. Sci. USA 17 Nov 2009 (doi:10.1073/pnas.0911512106).
50. Arias-Palomo, E., Recuero-Checa, M. A., Bustelo, X. R. & Llorca, O. 3D structure of Syk kinase determined by single-particle electron microscopy. Biochim. Biophys. Acta 1774, 1493-1499 (2007).
51. Adachi, T, Wienands, J., Tsubata, T. & Kurosaki, T Interdomain A is crucial for ITAM-dependent and-independent regulation of Syk. Biochem. Biophys. Res. Commun. 364, 111-117 (2007).
52. Rolli, V. et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol. Cell 10, 1057-1069 (2002).
53. Futterer, K., Wong, J., Grucza, R. A., Chan, A. C. & Waksman, G. Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J. Mol. Biol. 281, 523-537 (1998).
54. Grucza, R. A., Futterer, K., Chan, A. C. & Waksman, G. Thermodynamic study of the binding of the tandem-SH2 domain of the Syk kinase to a dually phosphorylated ITAM peptide: evidence for two conformers. Biochemistry 38, 5024-5033 (1999).
55. Fodor, S., Jakus, Z. & Mócsai, A. ITAM-based signaling beyond the adaptive immune response. Immunol. Lett. 104, 29-37 (2006).
56. Furlong, M. T. et al. Identification of the major sites of autophosphorylation of the murine protein-tyrosine kinase Syk. Biochim. Biophys. Acta 1355, 177-190 (1997).
57. Keshvara, L. M., Isaacson, C, Harrison, M. L. & Geahlen, R. L. Syk activation and dissociation from the B-cell antigen receptor is mediated by phosphorylation of tyrosine 130. J. Biol. Chem. 272, 10377-10381 (1997).
58. Zhang, Y et al. Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling. Proc. Natl Acad. Sci. USA 105, 11760-11765 (2008).
59. Hong, J. J., Yankee, T M., Harrison, M. L. & Geahlen, R. L. Regulation of signaling in B cells through the phosphorylation of Syk on linker region tyrosines. A mechanism for negative signaling by the Lyn tyrosine kinase. J. Biol. Chem. 277, 31703-31714 (2002).
60. 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. 164, 338-344 (2000).
61. Moon, K. D. et al. Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. J. Biol. Chem. 280, 1543-1551 (2004).
62. Simon, M., Vanes, L, Geahlen, R. L. & Tybulewicz, V L. Distinct roles for the linker region tyrosines of Syk in FceRI signaling in primary mast cells. J. Biol. Chem. 280, 4510-4517 (2005).
63. Brdicka, T., Kadlecek, T A., Roose, J. P., Pastuszak, A. W. & Weiss, A. Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases. Mol. Cell. Biol. 25, 4924-4933 (2005).
64. Kulathu, Y, Grothe, G. & Reth, M. Autoinhibition and adapter function of Syk. Immunol. Rev. 232, 286-299 (2009).
65. Zeitlmann, L. et al. T cell activation induced by novel gain-of-function mutants of Syk and ZAP-70. J. Biol. Chem. 273, 15445-15452 (1998).
66. Deckert, M., Tartare Deckert, S., Couture, C, Mustelin, T. & Altman, A. Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product. Immunity 5, 591-604 (1996).
67. Law, C. L, Chandran, K. A., Sidorenko, S. P. & Clark, E. A. Phospholipase C-y 1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. Mol. Cell. Biol. 16, 1305-1315 (1996).
68. Groesch, T D., Zhou, F, Mattila, S., Geahlen, R. L. & Post, C. B. Structural basis for the requirement of two phosphotyrosine residues in signaling mediated by Syk tyrosine kinase. J. Mol. Biol. 356, 1222-1236 (2006).
69. Zhang, J., Berenstein, E. & Siraganian, R. P. Phosphorylation of Tyr342 in the linker region of Syk is critical for FceRI signaling in mast cells. Mol. Cell. Biol. 22, 8144-8154 (2002).
70. Schymeinsky, J. et al. The Vav binding site of the nonreceptor tyrosine kinase Syk at Tyr 348 is critical for (32 integrin (CD 11/CD18)-mediated neutrophil migration. Blood 108, 3919-3927 (2006).
71. Kulathu, Y, Hobeika, E., Turchinovich, G. & Reth, M. The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development. EMBO J. 27, 1333-1344 (2008).
72. Mócsai, A., Zhou, M., Meng, F, Tybulewicz, V. L. & Lowell, C. A. Syk is required for integrin signaling in neutrophils. Immunity 16, 547-558 (2002).
73. Obergfell, A. et al. Coordinate interactions of Csk, Src, and Syk kinases with aIIb(33 initiate integrin signaling to the cytoskeleton. J. Cell Biol. 157, 265-275 (2002).
74. Clements, J. L. et al. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J. Clin. Invest. 103, 19-25 (1999).
75. Newbrough, S. A. et al. SLP-76 regulates Fcy receptor and integrin signaling in neutrophils. Immunity 19, 761-769 (2003).
76. 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr. Immunity 15, 507-519 (2001).
77. Mócsai, A. et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nature Immunol. 7, 1326-1333 (2006).
78. Zou, W., Reeve, J. L, Liu, Y., Teitelbaum, S. L. & Ross, F. P. DAP 12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol. Cell 31, 422-431 (2008).
79. Frommhold, D. et al. Spleen tyrosine kinase Syk is critical for sustained leukocyte adhesion during inflammation in vivo. BMC Immunol. 8, 31 (2007).
80. Hirahashi, J. et al. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25, 271-283 (2006).
81. syk protein tyrosine kinase by platelet integrin aIIb(33. EMBO J. 16, 6414-6425 (1997).
82. Woodside, D. G. et al. Activation of Syk protein tyrosine kinase through interaction with integrin (3 cytoplasmic domains. Curr. Biol. 11, 1799-1804 (2001).
83. Woodside, D. G. et al. The N-terminal SH2 domains of Syk and ZAP-70 mediate phosphotyrosine-independent binding to integrin (3 cytoplasmic domains. J. Biol. Chem. 277, 39401-39408 (2002).
84. Abtahian, F. et al. Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Mol. Cell. Biol. 26, 6936-6949 (2006).
85. Zou, W. et al. Syk, c-Src, the aV(33 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J. Cell Biol. 176, 877-888 (2007).
86. Graham, D. B. et al. An ITAM-signaling pathway controls cross-presentation of particulate but not soluble antigens in dendritic cells. J. Exp. Med. 204, 2889-2897 (2007).
87. Wakselman, S. et al. Developmental neuronal death in hippocampus requires the microglial CD 1 1b integrin and DAP12 immunoreceptor. J. Neurosci. 28, 8138-8143 (2008).
88. Boylan, B. et al. Identification of FcyRIIa as the ITAM-bearing receptor mediating aIIb(33 outside-in integrin signaling in human platelets. Blood 112, 2780-2786 (2008).
89. Urzainqui, A. et al. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity 17, 401-412 (2002).
90. Zarbock, A., Lowell, C. A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced aL(32 integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773-783 (2007).
91. Zarbock, A. et al. PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcRy to induce slow leukocyte rolling. J. Exp. Med. 205, 2339-2347 (2008).
92. Underhill, D. M., Rossnagle, E., Lowell, C. A. & Simmons, R. M. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 106, 2543-2550 (2005).
93. Gross, O. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433-436 (2009).
94. Goodridge, H. S., Simmons, R. M. & Underhill, D. M. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J. Immunol. 178, 3107-3115 (2007).
95. Slack, E. C. et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur. J. Immunol. 37, 1600-1612 (2007).
96. LeibundGut-Landmann, S. et al. Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature Immunol. 8, 630-638 (2007)
97. Brown, G. D. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nature Rev. Immunol. 6, 33-43 (2006).
98. Hara, H. et al. Cell type-specific regulation of ITAM-mediated NF-κB activation by the adaptors, CARMA1 and CARD9. J. Immunol. 181, 918-930 (2008).
99. Hara, H. et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nature Immunol. 8, 619-629 (2007).
100. Glocker, E. O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727-1735 (2009).
101. Leibundgut-Landmann, S., Osorio, F., Brown, G. D. & Reis e Sousa, C. Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 112, 4971-4980 (2008).
102. Robinson, M. J. et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J. Exp. Med. 206, 2037-2051 (2009).
103. Sato, K. et al. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor γ chain to induce innate immune responses. J. Biol. Chem. 281, 38854-38866 (2006).
104. Wells, C. A. et al. The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J. Immunol. 180, 7404-7413 (2008).
105. Yamasaki, S. et al. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc. Natl Acad. Sci. USA 106, 1897-1902 (2009).
106. Werninghaus, K. et al. Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ-Syk- Card9-dependent innate immune activation. J. Exp. Med. 206, 89-97 (2009).
107. Ishikawa, E. et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206, 2879-2888 (2009).
108. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229-265 (2009).
109. Shio, M. T. et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 5, e1000559 (2009).
110. Hise, A. G. et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 5, 487-497 (2009).
111. Schoenen, H. et al. Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J. Immunol. 184, 2756-2760 (2010).
112. Sarantis, H. & Gray-Owen, S. D. The specific innate immune receptor CEACAM3 triggers neutrophil bactericidal activities via a Syk kinase-dependent pathway. Cell. Microbiol. 9, 2167-2180 (2007).
113. Van Ziffle, J. A. & Lowell, C. A. Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection. Blood 114, 4871-4882 (2009).
114. Chen, S. T. et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453, 672-676 (2008).
115. Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunol. 9, 1179-1188 (2008).
116. Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899-903 (2009).
117. + dendritic cells and a subset of monocytes. J. Biol. Chem. 283, 16693-16701 (2008).
118. Awasaki, T. et al. Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 50, 855-867 (2006).
119. Ford, J. W. & McVicar, D. W. TREM and TREM-like receptors in inflammation and disease. Curr. Opin. Immunol. 21, 38-46 (2009).
120. Tassiulas, I. et al. Amplification of IFN-a-induced STAT 1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature Immunol. 5, 1181-1189 (2004).
121. Hida, S. et al. Fc receptor y-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nature Immunol. 10, 214-222 (2009).
122. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and (3-catenin. Nature Immunol. 10, 734-743 (2009).
123. Lang, P. et al. TCR-induced transmembrane signaling by peptide/MHC class II via associated Ig-a/p dimers. Science 291, 1537-1540 (2001).
124. McVicar, D. W. et al. DAP 12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J. Biol. Chem. 273, 32934-32942 (1998).
125. Zompi, S. et al. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP 12 or Syk family kinases. Nature Immunol. 4, 565-572 (2003).
126. Billadeau, D. D., Upshaw, J. L., Schoon, R. A., Dick, C. J. & Leibson, P. J. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nature Immunol. 4, 557-564 (2003).
127. Ng, G. et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29, 807-818 (2008).
128. Mócsai, A. et al. G-protein-coupled receptor signaling in Syk-deficient neutrophils and mast cells. Blood 101, 4155-4163 (2003).
129. Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP 12) result in a presenile dementia with bone cysts. Nature Genet. 25, 357-361 (2000).
130. Kaifu, T. et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111, 323-332 (2003).
131. Humphrey, M. B. et al. The signaling adapter protein DAP 12 regulates multinucleation during osteoclast development. J. Bone Miner. Res. 19, 224-234 (2004).
132. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758-763 (2004).
133. -/- osteoclast phenotype. J. Cell Biochem. 90, 871-883 (2003).
134. May, F et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 114, 3464-3472 (2009).
135. Bezman, N. A. et al. Requirements of SLP76 tyrosines in ITAM and integrin receptor signaling and in platelet function in vivo. J. Exp. Med. 205, 1775-1788 (2008).
136. Sebzda, E. et al. Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev Cell 11, 349-361 (2006).
137. + leukocytes. Dev. Cell 18, 437-449 (2010).
138. Carramolino, L. et al. Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis. Circ. Res. 106, 1197-1201 (2010).
139. Bertozzi, C. C. et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 2 Apr 2010 (doi:10.1182/blood-2010-02- 270876).
140. Fu, J. et al. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J. Clin. Invest. 118, 3725-3737 (2008).
141. Uhrin, P. et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 8 Jan 2010 (doi:10.1182/blood-2009-04-216069).
142. Suzuki-Inoue, K. et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J. Biol. Chem. 282, 25993-26001 (2007).
143. Coopman, P. J. et al. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406, 742-747 (2000).
144. Coopman, P. J. & Mueller, S. C. The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett. 241, 159-173 (2006).
145. Yanagi, S., Inatome, R., Takano, T. & Yamamura, H. Syk expression and novel function in a wide variety of tissues. Biochem. Biophys. Res. Commun. 288, 495-498 (2001).
146. Beckmann, S., Buro, C., Dissous, C., Hirzmann, J. & Grevelding, C. G. The Syk kinase SmTK4 of Schistosoma mansoni is involved in the regulation of spermatogenesis and oogenesis. PLoS Pathog. 6, e1000769 (2010).
147. Jakus, Z., Simon, E., Balázs, B. & Mócsai, A. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum. 3 Mar 2010 (doi:10.1002/art.27438).
148. Meltzer, E. O., Berkowitz, R. B. & Grossbard, E. B. An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J. Allergy Clin. Immunol. 115, 791-796 (2005).
149. Braselmann, S. et al. R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammation. J. Pharmacol. Exp. Ther. 319, 998-1008 (2006).
150. Pine, P. R. et al. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin. Immunol. 124, 244-257 (2007).
151. Weinblatt, M. E. et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 58, 3309-3318 (2008).
152. Podolanczuk, A., Lazarus, A. H., Crow, A. R., Grossbard, E. & Bussel, J. B. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 113, 3154-3160 (2009).
153. Goodman, P. A., Wood, C. M., Vassilev, A., Mao, C. & Uckun, F. M. Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia. Oncogene 20, 3969-3978 (2001).
154. Jumaa, H. et al. Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature 423, 452-456 (2003).
155. Flemming, A., Brummer, T., Reth, M. & Jumaa, H. The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansion. Nature Immunol. 4, 38-43 (2003).
156. Wossning, T. et al. Deregulated Syk inhibits differentiation and induces growth factor-independent proliferation of pre-B cells. J. Exp. Med. 203, 2829-2840 (2006).
157. Uckun, F. M., Ek, R. O., Jan, S. T., Chen, C. L. & Qazi, S. Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic. Br. J. Haematol. 11 Feb 2010 (doi:10.1111/j.1365-2141.2010.08106.x).
158. Monroe, J. G. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nature Rev. Immunol. 6, 283-294 (2006).
159. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88-92 (2010).
160. Gururajan, M., Jennings, C. D. & Bondada, S. Cutting edge: constitutive B cell receptor signaling is critical for basal growth of B lymphoma. J. Immunol. 176, 5715-5719 (2006).
161. Buchner, M. et al. Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res. 69, 5424-5432 (2009).
162. Carsetti, L. et al. Phosphorylation of the activation loop tyrosines is required for sustained Syk signaling and growth factor-independent B-cell proliferation. Cell Signal. 21, 1187-1194 (2009).
163. Buchner, M. et al. Spleen tyrosine kinase inhibition prevents chemokine-and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 24 Mar 2010 (doi:10.1182/blood-2009-07-233692).
164. Chen, L. et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 111, 2230-2237 (2008).
165. Young, R. M. et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood 11 3, 2508-2516 (2009).
166. Friedberg, J. W. et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 11 5, 2578-2585 (2010).
167. Feldman, A. L. et al. Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia 22, 1139-1143 (2008).
168. Streubel, B., Vinatzer, U., Willheim, M., Raderer, M. & Chott, A. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 20, 313-318 (2006).
169. Wilcox, R. A. et al. Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin's lymphoma cell lines. Leukemia 24, 229-232 (2009).
170. Kuno, Y. et al. Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 97, 1050-1055 (2001). (Pubitemid 32154292)
171. Hahn, C. K. et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 16, 281-294 (2009).
172. Lanier, L. L. Viral immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling in cell transformation and cancer. Trends Cell Biol. 16, 388-390 (2006).
173. Morrison, J. A. & Raab-Traub, N. Roles of the ITAM and PY motifs of Epstein-Barr virus latent membrane protein 2A in the inhibition of epithelial cell differentiation and activation of β-catenin signaling. J. Virol. 79, 2375-2382 (2005).
174. Lu, J. et al. Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells. J. Biol. Chem. 281, 8806-8814 (2006).
175. Katz, E. et al. MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J. Exp. Med. 201, 431-439 (2005).
176. Ross, S. R. et al. An immunoreceptor tyrosine activation motif in the mouse mammary tumor virus envelope protein plays a role in virus-induced mammary tumors. J. Virol. 80, 9000-9008 (2006).
177. Lagunoff, M., Lukac, D. M. & Ganem, D. Immunoreceptor tyrosine-based activation motif-dependent signaling by Kaposi's sarcoma-associated herpesvirus K1 protein: effects on lytic viral replication. J. Virol. 75, 5891-5898 (2001). (Pubitemid 32553119)
178. Lee, B. S. et al. Characterization of the Kaposi's sarcoma-associated herpesvirus K1 signalosome. J. Virol. 79, 12173-12184 (2005).
179. Amarante, M. K. & Watanabe, M. A. The possible involvement of virus in breast cancer. J. Cancer Res. Clin. Oncol. 135, 329-337 (2009).
180. Yuan, Y. et al. Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin. Cancer Res. 12, 6687-6695 (2006).
181. Layton, T., Stalens, C., Gunderson, F., Goodison, S. & Silletti, S. Syk tyrosine kinase acts as a pancreatic adenocarcinoma tumor suppressor by regulating cellular growth and invasion. Am. J. Pathol. 175, 2625-2636 (2009).
182. Muthusamy, V. et al. Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 66, 11187-11193 (2006).
183. Wang, L., Devarajan, E., He, J., Reddy, S. P. & Dai, J. L. Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression. Cancer Res. 65, 10289-10297 (2005).
184. Nakashima, H. et al. Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer. Cancer Lett. 236, 89-94 (2006).
185. Wang, L. et al. Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res. 63, 4724-4730 (2003).
186. Steele, R. E., Stover, N. A. & Sakaguchi, M. Appearance and disappearance of Syk family protein-tyrosine kinase genes during metazoan evolution. Gene 239, 91-97 (1999).
187. Suga, H. et al. Extensive gene duplication in the early evolution of animals before the parazoan-eumetazoan split demonstrated by G proteins and protein tyrosine kinases from sponge and hydra. J. Mol. Evol. 48, 646-653 (1999). (Pubitemid 29287954)
188. Ruvkun, G. & Hobert, O. The taxonomy of developmental control in Caenorhabditis elegans. Science 282, 2033-2041 (1998).
189. Saijo, K. et al. Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development. Nature Immunol. 4, 274-279 (2003).
190. Yasuda, T. et al. Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity 28, 499-508 (2008).