syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction
Open accessAbstract
Activation of the syk tyrosine kinase occurs almost immediately following engagement of many types of antigen receptors, including Fc receptors, but the mechanism through which syk is activated is currently unclear. Here we demonstrate that Fc receptor-induced syk activation occurs as the result of phosphorylation of the syk activation loop by both src family kinases and other molecules of activated syk, suggesting that syk activation occurs as the result of a src kinase-initiated activation loop phosphorylation chain reaction. This type of activation mechanism predicts that syk activation would exhibit exponential kinetics, providing a potential explanation for its rapid and robust activation by even weak antigen receptor stimuli. We propose that a similar mechanism may be responsible for generating rapid activation of other cytoplasmic tyrosine kinases, such as those of the Bruton tyrosine kinase/tec family, as well.
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Once recruited to the DAP12 ITAM motif, Syk is phosphorylated by Src on its activation loop and this then initiates an autophosphorylation of other Syk molecules.
“Once recruited to the DAP12 ITAM motif, Syk is phosphorylated by Src on its activation loop and this then initiates an autophosphorylation of other Syk molecules [69]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [69]
The Discussion describes a Src-family kinase initiating Syk activation-loop phosphorylation, followed by activated Syk phosphorylating other Syk molecules. The study examines Fc receptor-induced activation, however, and does not establish the claimed recruitment to a DAP12 ITAM motif. (LLM, conf=0.87)
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“subunits of the Fc eRI), Y518F- and Y519F-mutated Syk expressed by recombinant vaccinia viruses has basal activity nearly identical to that of wild-type Syk but reduced tyrosine phosphorylation and no increase in activity after Fc eRI aggregation (17).”
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“In contrast, the two adjacent activation loop tyrosines in the catalytic domain of Syk (Tyr519 and Tyr520 in rat Syk) are essential for propagating receptorinduced downstream signaling ( 13 , 29, 60).”
BackgroundModeling the early signaling events mediated by FcεRI
Goldstein, B., Faeder, J. R., Hlavacek, W. S., Blinov, M. L., Redondo, A., & Wofsy, C. (2002) · Molecular Immunology · doi:10.1016/s0161-5890(02)00066-4 · Cited by 57 · see citing works
“There is indirect evidence that autophosphorylation of Syk is trans ( El-Hillal et al., 1997 ), however, for the”
BackgroundTedder, T. F., Poe, J. C., Fujimoto, M., et al. (2004) · KARGER eBooks · doi:10.1159/000082087 · Cited by 56 · see citing works
Gong, Q., White, L. S., Johnson, R., et al. (1997) · Immunity · doi:10.1016/s1074-7613(00)80358-1 · Cited by 54 · see citing works
Regulation and Function of Syk Tyrosine Kinase in Mast Cell Signaling and Beyond
de Castro, R. O. (2011) · Journal of Signal Transduction · doi:10.1155/2011/507291 · Cited by 54 · see citing works
“It is suggested that phosphorylation of the activation loop tyrosines occurs mostly by auto-transphosphorylation with some participation of other tyrosine kinases in the initiation of the phosphorylation process [40, 59].”
BackgroundA CD19-Dependent Signaling Pathway Regulates Autoimmunity in Lyn-Deficient Mice
Hasegawa, M., Fujimoto, M., Poe, J. C., Steeber, D. A., Lowell, C. A., & Tedder, T. F. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.5.2469 · Cited by 53 · see citing works
“Since Syk phosphorylation and kinase activity can be upregulated through an efficient autophosphorylation loop (50), BCR-induced Fyn activation may be sufficient to activate Syk in the absence of CD19-mediated Src family PTK amplification.”
BackgroundA current understanding of FcɛRI-dependent mast cell activation
Rivera, J., & Olivera, A. (2008) · Current Allergy and Asthma Reports · doi:10.1007/s11882-008-0004-z · Cited by 47 · see citing works
“Its binding and its ability to activate other Syk molecules through transphosphorylation are essential for signal amplification [ 20 ].”
BackgroundMolecular Dissection of the FcRβ Signaling Amplifier
On, M., Billingsley, J. M., Jouvin, M., & Kinet, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404890200 · Cited by 47 · see citing works
Self-citationComplementary Roles for CD19 and Bruton’s Tyrosine Kinase in B Lymphocyte Signal Transduction
Fujimoto, M., Poe, J. C., Satterthwaite, A. B., Wahl, M. I., Witte, O. N., & Tedder, T. F. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.11.5465 · Cited by 47 · see citing works
“2B) that may primarily rely on a Syk-dependent signal transduction pathway since Syk phosphorylation and kinase activity are intact in CD19 / B cells following BCR ligation, CD19 ligation does not induce detectable Syk activation in primary B cells (42), and BCRassociated Src family PTKs initiate a Syk autophosphoryla…”
BackgroundMatrix Valency Regulates Integrin-mediated Lymphoid Adhesion via Syk Kinase
Stupack, D. G., Li, E., Silletti, S., Kehler, J. A., Geahlen, R. L., Hahn, K. M., Nemerow, G. R., & Cheresh, D. A. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.4.777 · Cited by 47 · see citing works
Torres, A. J., Vasudevan, L., Holowka, D., & Baird, B. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802138105 · Cited by 45 · see citing works
“We treated cells with two different inhibitors of Syk kinase that is activated by clustered IgE-Fc RI after receptor phosphorylation by Lyn kinase (12).”
MethodGrucza, R. A., Bradshaw, J. M., F�tterer, K., & Waksman, G. (1999) · Medicinal Research Reviews · doi:10.1002/(sici)1098-1128(199907)19:4 · Cited by 43 · see citing works
Effector-induced Syk-mediated phosphorylation in human erythrocytes
Bordin, L., Ion-Popa, F., Brunati, A. M., Clari, G., & Low, P. S. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2004.12.010 · Cited by 42 · see citing works
“lane a), which has been described to be representative of syk activation [28].”
BackgroundWilleke, T., Schymeinsky, J., Prange, P., Stefan Zahler, A., & Walzog, B. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0102016 · Cited by 39 · see citing works
“Willeke et al. Syk controls the binding cycle of 2 integrins 7 and designated as an activation loop phosphorylation chain reaction [ 36 ].”
BackgroundHuu, D. L., Kimura, H., Date, M., et al. (2014) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2014.02.008 · Cited by 37 · see citing works
Leeansyah, E., Wines, B. D., Crowe, S. M., & Jaworowski, A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.2.1096 · Cited by 37 · see citing works
Xu, R. X., Seger, R., & Pecht, I. (1999) · PubMed · Cited by 36 · see citing works
Xu, R., Seger, R., & Pecht, I. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.3.1110 · Cited by 35 · see citing works
Quantifying Aggregation of IgE-FcϵRI by Multivalent Antigen
Hlavacek, W. S., Perelson, A. S., Sulzer, B., et al. (1999) · Biophysical Journal · doi:10.1016/s0006-3495(99)77397-2 · Cited by 34 · see citing works
“Aggregation of FceRI, which is constitutively associated with the protein tyrosine kinase Lyn (Eiseman and Bolen, 1992), then leads to a series of events, which include recruitment of additional Lyn kinases (El-Hillal et al., 1997; Wofsy et al., 1997).”
BackgroundStepanek, O., Draber, P., Drobek, A., Horejsi, V., & Brdicka, T. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202401 · Cited by 31 · see citing works
“concerning the identity of the kinases phosphorylating Syk (17, 18, 37, 63).”
BackgroundYamashita, T., Suzuki, R., Backlund, P. S., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802679200 · Cited by 31 · see citing works
Abl Family Kinases Regulate FcγR-Mediated Phagocytosis in Murine Macrophages
Greuber, E. K., & Pendergast, A. M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200974 · Cited by 29 · see citing works
“Syk activation is more efficient, however, when also phosphorylated in trans by other kinases (52, 53).”
BackgroundLee, J. H., Kim, Y. M., Kim, N. W., Kim, J. W., Her, E., Kim, B. K., Kim, J. H., Ryu, S. H., Park, J. W., Seo, D. W., et al. (2006) · Blood · doi:10.1182/blood-2005-10-009159 · Cited by 31 · see citing works
Protein tyrosine kinase Syk modulates EGFR signalling in human mammary epithelial cells
Ruschel, A., & Ullrich, A. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.03.007 · Cited by 30 · see citing works
Rigby, S., Huang, Y., Streubel, B., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.034272 · Cited by 29 · see citing works
Physical and Functional Interaction between p72 and Erythropoietin Receptor
Duprez, V., Blank, U., Chrétien, S., Gisselbrecht, S., & Mayeux, P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.33985 · Cited by 28 · see citing works
Role of phosphoinositide 3-kinase signaling in mast cells: new insights from knockout mouse studies
Fukao, T., Terauchi, Y., Kadowaki, T., & Koyasu, S. (2003) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0475-2 · Cited by 28 · see citing works
“Subsequently, phosphorylated ITAMs in the FceRIβ subunit promote further recruitment of Lyn whereas ITAMs present in the FceRIγ subunit recruit Syk kinase [81, 82 ].”
BackgroundSRC-Family Kinases in Acute Myeloid Leukaemia and Mastocytosis
Voisset, E., Brenet, F. A., Lopez, S., et al. (2020) · Cancers · doi:10.3390/cancers12071996 · Cited by 27 · see citing works
“LYN is then required for the transphosphorylation of FcεRI ITAMs (immunoreceptor tyrosine-based activation motifs), for the activation of SYK, another protein kinase crucial for the phosphorylation of the adaptor LAT, and for the full assembly of the FcεRI signaling framework [102,103].”
BackgroundFc receptor targeting in the treatment of allergy, autoimmune diseases and cancer
Nakamura, A., Akiyama, K., & Takai, T. (2005) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.9.1.169 · Cited by 27 · see citing works
“Then, the phosphorylated ITAMs serve the binding site of Syk, resulting in the conformational change of Syk, and then leading to its activation and autophosphorylation [44,45].”
BackgroundCD19 and CD22 Regulate a B Lymphocyte Signal Transduction Pathway That Contributes to Autoimmunity.
Tedder, T. F., Sato, S., Poe, J. C., et al. (2000) · The Keio Journal of Medicine · doi:10.2302/kjm.49.1 · Cited by 27 · see citing works
Wong, J., Straus, D. B., & Chan, A. C. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.5.2855 · Cited by 27 · see citing works
“Enzymatic activation of the KS(YYFF) mutant was slightly decreased compared to that of the KS chimera, consistent with the ability of Syk to contribute to autoactivation (20).”
BackgroundResultKitaura, J., Kawakami, Y., Maeda‐Yamamoto, M., Hořejšı́, V., & Kawakami, T. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.1.455 · Cited by 24 · see citing works
“3B), consistent with the previous study demonstrating that the full activation of Syk requires Lyn and Syk activity in mast cells (26).”
ResultSarkar, S., Svoboda, M., de Beaumont, R., et al. (2002) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/1042819021000003009 · Cited by 22 · see citing works
“Moreover, REH cells express very low levels of SYK, and many precursor B ALL cells do not express any detectable levels of SYK [41].”
BackgroundInfluentialNegative Regulation of FcϵRI-mediated Signaling and Mast Cell Function by the Adaptor Protein LAX
Zhu, M., Rhee, I., Liu, Y., & Zhang, W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601535200 · Cited by 22 · see citing works
Goldstein, B., Coombs, D., Faeder, J. R., et al. (2008) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-09789-3_8 · Cited by 21 · see citing works
Dauvillier, S., Mérida, P., Visintin, M., Cattaneo, A., Bonnerot, C., & Dariavach, P. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.5.2274 · Cited by 20 · see citing works
“The PTK Lyn has also been implicated in the regulation of Ag receptor-coupled Ca(2) mobilization (12, 16), and is essential for the phosphorylation of Fc RI- and Fc RIchains, and that of Syk and Btk, immediately after Fc RI stimulation (3, 10, 15, 34).”
BackgroundShikonin inhibits IgE-mediated histamine release by human basophils and Syk kinase activity
Takano‐Ohmuro, H., Yoshida, L. S., Yuda, Y., Morioka, K., & Kitani, S. (2008) · Inflammation Research · doi:10.1007/s00011-008-8067-9 · Cited by 19 · see citing works
“In the cell, autophosphorylation of Syk is proposed to occur by transphosphorylation of a Syk molecule bound to one receptor by another Syk bound to the adjacent receptor [ 26 , 27].”
BackgroundKambayashi, T., Okumura, M., Baker, R. G., et al. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00305-10 · Cited by 18 · see citing works
“Once phosphorylated, these chains serve as docking sites for several protein tyrosine kinases (PTKs), including Lyn and spleen tyrosine kinase (Syk) (9, 19, 34).”
BackgroundInnate immune signal transduction pathways to fungal infection: Components and regulation
Chen, T., & Gao, C. (2024) · Cell Insight · doi:10.1016/j.cellin.2024.100154 · Cited by 15 · see citing works
“The ITAM-based signaling events lead to the spleen tyrosine kinase (Syk) recruitment (El-Hillal et al., 1997), followed by caspase-recruitment domain (CARD)-mediated aggregation of CARD9 (Gross et al., 2006) with the adaptor protein B cell lymphoma 10 (BCL-10) and the associated mucosa-associated…”
BackgroundGetz, T. M., Mayanglambam, A., Daniel, J. L., et al. (2011) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04192.x · Cited by 17 · see citing works
Development of a high-throughput fluoroimmunoassay for Syk kinase and Syk kinase inhibitors
Yamamoto, N., Hasegawa, H., Seki, H., et al. (2003) · Analytical Biochemistry · doi:10.1016/s0003-2697(03)00026-5 · Cited by 17 · see citing works
Apoptosis of hepatic stellate cells mediated by specific protein nitration
Mòdol, T., Natal, C., de Obanos, M. P. P., Miguel, E. D. D., Iraburu, M. J., & López-Zabalza, M. J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.10.017 · Cited by 16 · see citing works
“Also Syk, a described substrate of Src kinases including Lyn [48,49], was”
BackgroundReal-Time Cross-Correlation Image Analysis of Early Events in IgE Receptor Signaling
Das, R., Hammond, S., Holowka, D., & Baird, B. A. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.105502 · Cited by 15 · see citing works
“Phosphorylated ITAMs on the γ subunit bind tandem Src-homology 2 (SH2) domains on the tyrosine kinase Syk which is activated through a conformational change and tyrosine phosphorylation (3, 4).”
Background
- Authors
- El-Hillal, O., Kurosaki, T., Yamamura, H., Kinet, J.-P., & Scharenberg, A. M.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-03-04
- Volume
- 94
- Issue
- 5
- Pages
- 1919-1924
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC20018
- OpenAlex
- W2036431526
- Cited by
- 130
- References
- 24
- Citations by year
- 2026: 1 · 2024: 6 · 2023: 2 · 2021: 1 · 2020: 4 · 2019: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 3
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Syk, kinase activation, Src family kinases, activation loop phosphorylation, Fc receptors, antigen receptor signaling, Bruton's tyrosine kinase, Tec family kinases
- MeSH terms
- Syk Kinase, Animals, Cell Line, Enzyme Activation, Enzyme Precursors, Gene Expression Regulation, Kinetics, Peptide Mapping, Phosphopeptides, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Fc, Swine, Transfection, Tyrosine, Vaccinia virus, Blotting, Western, 3T3 Cells, src Homology Domains, src-Family Kinases, Intracellular Signaling Peptides and Proteins, Mice
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