The Syk protein tyrosine kinase is essential for Fcγ receptor signaling in macrophages and neutrophils
Open accessAbstract
The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcgamma receptor (FcgammaR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk-/- embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcgammaR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcgammaR gamma chain, as well as Erk2 activation, was compromised in Syk-/- macrophages after FcgammaR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcgammaRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.
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Recruitment and activation of Syk is critical for FcγR-mediated phagocytosis, as shown by the inability of Syk−/− macrophages to internalize IgG-opsonized particles.
“Recruitment and activation of this tyrosine kinase is critical for FcγR-mediated phagocytosis, as demonstrated by the inability of macrophages from Syk−/− mice to internalize IgG-opsonized particles (Crowley et al. 1997; Kiefer et al. 1998).”
From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Kiefer et al. 1998
The Results report that Syk is important for FcγR-mediated uptake of IgG-opsonized red blood cells, but they do not show an inability to internalize them: 15% of Syk-deficient macrophages completed phagocytosis after 10 minutes. The Discussion likewise describes a significant reduction, not a complete loss. Page numbers were not available in our copy. (LLM, conf=0.90)
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Cites
Greenberg, S., Chang, P., & Silverstein, S. C. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)41945-4 · Cited by 237 · see citing works
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Research works printed but not linked: 3
- Cheng, A. M., I. Negishi, S. J. Anderson, A. C. Chan, J. Bolen, D. Y. Loh, and T. Pawson. 1997. The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling. Proc. Natl. Acad. Sci. USA 94:9797-9801.
- Greenberg, S., P. Chang, D. C. Wang, R. Xavier, and B. Seed. 1996. Clus- tered syk tyrosine kinase domains trigger phagocytosis. Proc. Natl. Acad. Sci. USA 93:1103-1107.
- Mallick-Wood, C. A., W. Pao, A. M. Cheng, J. M. Lewis, S. Kulkarni, J. B. Bolen, B. Rowley, R. E. Tigelaar, T. Pawson, and A. C. Hayday. 1996. Disruption of epithelial gamma delta T cell repertoires by mutation of the Syk tyrosine kinase. Proc. Natl. Acad. Sci. USA 93:9704-9709.
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The SYK tyrosine kinase: A crucial player in diverse biological functions
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Phagocytosis and the actin cytoskeleton
May, R. C., & Machesky, L. M. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.6.1061 · Cited by 715 · see citing works
Neutrophil cell surface receptors and their intracellular signal transduction pathways
Futosi, K., Fodor, S., & Mócsai, A. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.06.034 · Cited by 642 · see citing works
Phagocytosis: Receptors, signal integration, and the cytoskeleton
Freeman, S. A., & Grinstein, S. (2014) · Immunological Reviews · doi:10.1111/imr.12212 · Cited by 548 · see citing works
Self-citationLocalized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis
Botelho, R. J., Teruel, M., Dierckman, R., Anderson, R., Wells, A., York, J. D., Meyer, T., & Grinstein, S. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.151.7.1353 · Cited by 539 · see citing works
“Recruitment and activation of this tyrosine kinase is critical for Fc g R-mediated phagocytosis, as demonstrated by the inability of macrophages from Syk 2/2 mice to internalize IgG-opsonized particles (Crowley et al., 1997; Kiefer et al., 1998).”
BackgroundSelf-citationSyk is required for integrin signaling in neutrophils
Mócsai, A., Zhou, M., Meng, F., Tybulewicz, V. L., & Lowell, C. A. (2002) · Immunity · doi:10.1016/s1074-7613(02)00303-5 · Cited by 421 · see citing works
Role of Src kinases and Syk in Fcγ receptor-mediated phagocytosis and phagosome-lysosome fusion
Majeed, M., Caveggion, E., Lowell, C. A., & Berton, G. (2001) · Journal of Leukocyte Biology · doi:10.1189/jlb.70.5.801 · Cited by 97 · see citing works
Illouz, T., Nicola, R., Ben-Shushan, L., Madar, R., Biragyn, A., & Okun, E. (2021) · Communications Biology · doi:10.1038/s42003-021-01851-6 · Cited by 21 · see citing works
- Authors
- Kiefer, F., Brumell, J., Al-Alawi, N., Latour, S., Cheng, A., Veillette, A., Grinstein, S., & Pawson, T.
- Affiliations
- Mount Sinai Hospital (CA)
- McGill University (CA)
- Hospital for Sick Children (CA)
- Corresponding author
- Pawson, Tony
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1998-07-01
- Volume
- 18
- Issue
- 7
- Pages
- 4209-4220
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC109005
- OpenAlex
- W2127618101
- Cited by
- 376
- References
- 1
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 11 · 2020: 14 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 16 · 2015: 11 · 2014: 10 · 2013: 20 · 2012: 19
- FWCI
- 23.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- Fcγ receptor signaling, macrophages, neutrophils, ITAM, Src family kinases, phagocytosis, reactive oxygen species, ERK2 activation, nitric oxide synthase, cell adhesion, radiation chimeras, complement-mediated phagocytosis
- MeSH terms
- Abdomen, Amino Acid Sequence, Animals, Cells, Cultured, Enzyme Induction, Erythrocytes, Female, Hemorrhage, Immunoglobulin G, Interferon-gamma, Lipopolysaccharides, Macrophages, Mice, Inbred CBA, Mice, Inbred C57BL, Molecular Sequence Data, Neutrophils, Phagocytosis, Phosphorylation, Tyrosine, Signal Transduction, Bone Marrow Transplantation, Respiratory Burst, Receptors, IgG, Antigen Presentation, Mice, Knockout, Nitric Oxide Synthase, COS Cells, Receptor Protein-Tyrosine Kinases, Mice, Nitric Oxide Synthase Type II
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