Alternative titles; symbols
HGNC Approved Gene Symbol: SYK
Cytogenetic location: 9q22.2 Genomic coordinates (GRCh38): 9:90,801,600-90,898,549 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.2 | Immunodeficiency 82 with systemic inflammation | 619381 | Autosomal dominant | 3 |
The SYK gene encodes a protein-tyrosine kinase expressed in immunologic cells and epithelial cells of the gastrointestinal mucosa. It plays an important role in the intracellular immune signaling cascade downstream from immuno- and other cell-surface receptors. In particular, SYK is an essential regulator of B-cell development and function, as well as a regulator of B-cell receptor (BCR)-mediated signaling (summary by Wang et al., 2021 and Aksentijevich, 2021).
The pig protein-tyrosine kinase SYK, with a relative molecular mass of 72,000, was first described as a protein predominantly expressed in the spleen and thymus (Zioncheck et al., 1988). The nucleotide and deduced amino acid sequence indicated that SYK is a member of the family of nonreceptor type kinases (Taniguchi et al., 1991). Muller et al. (1994) cloned the human homolog. They found an open reading frame of 1,890 bp encoding a protein of 630 amino acids, in comparison with the pig SYK of 628 amino acids. In the human protein, the N-terminal SH2 domain spans amino acids 10-102, the C-terminal SH2 domain spans amino acids 163-254, and the kinase domain includes amino acids 366-621. On the amino acid level, the overall similarity between human and pig SYK is 93%. The similarity was highest in the kinase domain.
Toyabe et al. (2001) determined that a subpopulation of T cells can express high levels of SYK and partially compensate for loss of T-cell functions in patients with deficiency of ZAP70 (176947).
SYK is a protein-tyrosine kinase that is widely expressed in hematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. SYK expression has been reported in cell lines of epithelial origin. Coopman et al. (2000) showed that SYK is commonly expressed in normal human breast tissue, benign breast lesions, and low-tumorigenic breast cancer cell lines. SYK mRNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wildtype SYK into an SYK-negative breast cancer cell line markedly inhibited its tumor growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient SYK in an SYK-positive breast cancer cell line significantly increased its tumor incidence and growth. Suppression of tumor growth by the reintroduction of SYK appeared to be the result of aberrant mitosis and cytokinesis. Coopman et al. (2000) proposed that SYK is a potent modulator of epithelial cell growth and a potential tumor suppressor in human breast carcinomas.
Inatome et al. (2001) found increased expression of SYK in human umbilical vein epithelial cells (HUVEC) during cell growth and in response to serum following serum deprivation. A porcine kinase-minus mutant of SYK, carrying a point mutation in the ATP-binding site, suppressed proliferation and survival when transfected into HUVEC cells. Overexpression of the kinase-minus mutant suppressed ERK (EPHB2; 600997) activation in these cells, whereas overexpression of the wildtype porcine SYK induced ERK activation. Inatome et al. (2001) suggested that SYK has a role in endothelial cell growth and survival as well as in the ERK signaling pathway.
Using flow cytometric, Western blot, and RT-PCR analyses, Siegel et al. (2006) showed that mice lacking Ocab (POU2AF1; 601206) had an altered distribution of bone marrow B cells and compromised pre-B cell receptor differentiation and signaling. Quantitative PCR and immunoblot analysis revealed reduced Syk expression in Ocab -/- cells. Immunofluorescence and immunoprecipitation analysis showed that Syk and Ocab colocalized in cytoplasm and interacted directly. Siegel et al. (2006) suggested that, together with dysregulation of other OCAB target genes, altered regulation of SYK may help explain the magnitude of defects observed in B-cell development, including the pre-B1-to-pre-B2 transition, and immune responses in Ocab -/- mice.
Gross et al. (2009) demonstrated that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL1-beta (147720) synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signaling for pro-IL1-beta synthesis selectively uses the Card9 (607212) pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmacologic inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (606416) was identified as the critical NOD (see 605980)-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (PYCARD; 606838) for caspase-1 (CASP1; 147678) activation and pro-IL1-beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, Gross et al. (2009) showed that Nlrp3-deficient mice are hypersusceptible to C. albicans infection. Thus, Gross et al. (2009) concluded that their results demonstrated the molecular basis for IL1-beta production after fungal infection and identified a crucial function for the Nlrp3 inflammasome in mammalian host defense in vivo.
Lee et al. (2012) showed that the atypical (i.e., nontuberculous) mycobacterium M. abscessus (Mabc) robustly activated the NLRP3 inflammasome in human macrophages via dectin-1 (CLEC7A; 606264)/SYK-dependent signaling and the cytoplasmic scaffold protein SQSTM1 (601530). Both dectin-1 and TLR2 (603028) were required for Mabc-induced expression of IL1B (147720), CAMP (600474), and DEFB4 (DEFB4A; 602215). Dectin-1-dependent SYK signaling, but not MYD88 (602170) signaling, led to activation of CASP1 and secretion of IL1B through a potassium efflux-dependent NLRP3/ASC inflammasome. Mabc-induced SQSTM1 expression was also critically involved in NLRP3 inflammasome activation. Lee et al. (2012) concluded that the NLRP3/ASC inflammasome is critical for antimicrobial responses and innate immunity to Mabc infection.
Ku et al. (1994) used isotopic in situ hybridization to demonstrate that the SYK gene is located on 9q22 in the human and chromosome 13 in the mouse.
Immunodeficiency 82 with Systemic Inflammation
In 6 patients from 5 unrelated families with immunodeficiency-82 with systemic inflammation (IMD82; 619381), Wang et al. (2021) identified heterozygous missense mutations in the SYK gene (see, e.g., S550Y, 600085.0001; S550F, 600085.0002; and P342T, 600085.0003). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; subsequent mutations (P342T, M450I, and A353T) were identified by screening for SYK variants in a larger cohort of patients with a similar phenotype. Most of the variants were not present in multiple public databases, including gnomAD, although 2 that were identified in patients with later onset were present at low frequencies in ExAC or gnomAD. The mutation occurred de novo in 2 patients and was transmitted from an affected parent in family 2; the pattern of inheritance could not be determined in 2 patients (patients 5 and 6). In vitro functional expression studies in transfected HEK293 cells showed that all the missense mutations caused significantly increased phosphorylation of SYK tyr525-526, consistent with constitutive activation and a gain-of-function effect. This was associated with enhanced downstream signaling as measured by increased ERK (see 601795) phosphorylation and exaggerated NFKB (see 164011) activity after stimulation. Similarly increased signaling and cytokine production were also observed in human SW480 human colonic epithelial cells that were stimulated by microbe-associated beta-(1,3)-glucans surface molecules from zymosan and curdlan. Although SYK is not expressed in T cells, studies of T cells derived from 1 patient showed secondary alterations in the T-cell compartment, such as decreased CD4:CD8 ratio, increased CD4 and CD8 memory T-cells, and increased frequency of certain cytokine-secreting cell subtypes. Many of the cellular abnormalities could be rescued by treatment with fostamatinib, which inhibits SYK. Mice with an orthologous Syk mutation developed a similar phenotype (see ANIMAL MODEL), except for the absence of gastrointestinal inflammation, which was prominent in human patients. The authors suggested that the gut inflammation in humans requires exposure to microorganisms.
Role in Cancer Development
Zhang et al. (2012) showed that the retinoblastoma (180200) genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 (614041) loss in retinoblastoma, Zhang et al. (2012) performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. Zhang et al. (2012) then evaluated the role of RB1 in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. For example, the protooncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, Zhang et al. (2012) concluded that retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.
Colucci et al. (2002) noted that humans with mutations in ZAP70 have T-cell immunodeficiency, that mice lacking Zap70 have blocked T-cell development, and that mice lacking Syk have a failure of B-cell development. NK cells express both molecules, which associate with immunoreceptor tyrosine-based activation motifs (ITAMs). Using mice deficient in both Zap70 and Syk, Colucci et al. (2002) observed NK cell activity comparable to that in wildtype mice. The mutant cells expressed Nkg2d (602893) and were able to lyse targets with and without Nkg2d ligands in vitro and in vivo. However, wildtype cells, but not the double-deficient cells, responded to CD16 (146740) and Ly49d (see 604274) cross-linking with increased cytotoxicity, suggesting that these 2 ITAM-bearing receptors are unable to signal in the mutant cells. Inhibitors of PI3K (see 601232) or Src kinases blocked and, in combination, abrogated cytotoxic activity in the mutant cells, whereas inhibition of both kinases was required to reduce wildtype NK activity. Colucci et al. (2002) concluded that intracellular signaling in the adaptive immune system, i.e., in B and T cells, is fundamentally different from that in the NK cells of the innate immune system.
Mocsai et al. (2002) generated bone marrow chimera mice by injecting Syk -/- fetal liver cells into lethally irradiated recipients. Neutrophils from Syk-deficient mice, like those from Cd18 (Itgb2; 600065)-deficient mice, failed to undergo respiratory burst, degranulation, or spreading in response to proinflammatory stimuli (e.g., TNF; 191160) while adherent to immobilized integrin ligands (Cd18). TNF stimulation of wildtype neutrophils adherent to fibrinogen (see FGA; 134820) enhanced Syk phosphorylation. Immunofluorescent microscopy demonstrated temporary colocalization of Syk and Cd18 during cell spreading. However, Syk -/- neutrophils had no defect in integrin-dependent migration. Mocsai et al. (2002) concluded that integrins use different signaling mechanisms to support migration and adherent activation.
Abtahian et al. (2003) identified a failure to separate emerging lymphatic vessels from blood vessels in mice lacking the hematopoietic signaling protein Slp76 (601603) or Syk. Blood-lymphatic connections led to embryonic hemorrhage and arteriovenous shunting. Expression of Slp76 could not be detected in endothelial cells, and blood-filled lymphatics also arose in wildtype mice reconstituted with Slp76-deficient bone marrow. Abtahian et al. (2003) concluded that their studies revealed a hematopoietic signaling pathway required for separation of the 2 major vascular networks in mammals. Absence of Slp76 usually results in embryonic hemorrhage and perinatal death in addition to loss of immune receptor signaling. However, Abtahian et al. (2003) observed that Slp76-deficient mice that survive to adulthood have cardiomegaly by 12 weeks of age due to elevated cardiac output. Slp76-deficient animals were not anemic, and analysis of Slp76-deficient hearts revealed no structural cardiac abnormality. Examination of the peripheral vasculature in Slp76-deficient mice revealed a network of dilated and tortuous blood vessels throughout the small intestine, which were shown to mediate arteriovenous shunting of blood. A cutaneous hemorrhagic appearance, first noted in midgestation, is the most striking phenotype observed in mouse embryos lacking Syk, Slp76, or PLC-gamma-2 (600220). Abtahian et al. (2003) noted that the pattern and timing of this phenotype closely resembled that of developing cutaneous lymphatics first described by Sabin (1901). Histologic analysis of the skin of Slp76-deficient embryos revealed that most of the blood observed was not extravasated hemorrhage but instead was contained within thin-walled vessels that stained weakly for the endothelial marker CD31 (173445) and not at all for smooth muscle actin (see 102540), features consistent with lymphatic vessels.
Faccio et al. (2005) observed diminished Vav3 (605541) phosphorylation in Syk-deficient preosteoclasts in vitro. Vav3 +/- Syk +/- mice had increased bone mass, and Vav3 +/- Syk +/- osteoclasts did not resorb bone in vitro. Faccio et al. (2005) concluded that SYK is a crucial upstream regulator of VAV3 in osteoclasts.
Zou et al. (2007) found that Syk -/- mouse osteoclasts failed to organize their cytoskeletons and had arrested bone-resorptive capacity, resulting in increased skeletal mass in Syk -/- embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lacked Syk. Bone resorption was mediated by a signaling complex including Syk, Src (190090), and integrin alpha-V (ITGAV; 193210)/beta-3 (ITGB3; 173470) in conjunction with ITAM-bearing proteins.
Wang et al. (2021) found that mice with a heterozygous S544Y Syk mutation, orthologous to S550Y in humans, developed spontaneous inflammatory arthritis and bony erosion of the ankles and tail. Gastrointestinal inflammation was not observed. This phenotype was associated with low IgG, high IgM, and variable B- and T-cell abnormalities. Analysis of ankle joint tissue and intestinal epithelial cells in mutant mice showed increased Syk phosphorylation. The authors noted that the bony erosion may be due to both hyperinflammation and dysregulated osteoclast differentiation. Treatment with an Syk inhibitor or bone marrow transplantation resulted in significant clinical improvement.
In a Chinese girl (patient 1) with immunodeficiency-82 with systemic inflammation (IMD82; 619381), Wang et al. (2021) identified a de novo heterozygous c.1649C-A transversion (c.1649C-A, NM_003177.6) in the SYK gene, resulting in a ser550-to-tyr (S550Y) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including ExAC and gnomAD. Patient peripheral blood cells and intestinal biopsy samples showed spontaneous phosphorylation of SYK despite a decrease in SYK expression levels. In vitro functional expression studies showed that the mutation resulted in a constitutively active and enhanced downstream signaling response compared to wildtype SYK, consistent with a gain of function.
In a girl (patient 2), born of unrelated Ashkenazi Jewish parents, with immunodeficiency-82 with systemic inflammation (IMD82; 619381), Wang et al. (2021) identified a heterozygous c.1649C-T transition (c.1649C-T, NM_003177.6) in the SYK gene, resulting in a ser550-to-phe (S550F) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her affected father (patient 3). It was not present in public databases, including ExAC and gnomAD. In vitro functional expression studies showed that it resulted in a constitutively active and enhanced downstream signaling response compared to wildtype SYK, consistent with a gain of function.
In a woman of Hungarian origin (patient 4) with immunodeficiency-82 with systemic inflammation (IMD82; 619381), Wang et al. (2021) identified a de novo heterozygous mutation in the SYK gene, resulting in pro342-to-thr (P342T) substitution at a conserved residue in the linker region that maintains SYK in an autoinhibited conformation. The mutation, which was found by direct screening of the SYK gene, was not present in several public databases, including ExAC and gnomAD. In vitro functional expression studies showed that it resulted in a constitutively active and enhanced downstream signaling response compared to wildtype SYK, consistent with a gain of function.
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Aksentijevich, I. The sickening consequences of too much SYK signaling. Nature Genet. 53: 432-434, 2021. [PubMed: 33782606] [Full Text: https://doi.org/10.1038/s41588-021-00837-8]
Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nature Immun. 3: 288-294, 2002. [PubMed: 11836527] [Full Text: https://doi.org/10.1038/ni764]
Coopman, P. J. P., Do, M. T. H., Barth, M., Bowden, E. T., Hayes, A. J., Basyuk, E., Blancato, J. K., Vezza, P. R., McLeskey, S. W., Mangeat, P. H., Mueller, S. C. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406: 742-747, 2000. [PubMed: 10963601] [Full Text: https://doi.org/10.1038/35021086]
Faccio, R., Teitelbaum, S. L., Fujikawa, K., Chappel, J., Zallone, A., Tybulewicz, V. L., Ross, F. P., Swat, W. Vav3 regulates osteoclast function and bone mass. Nature Med. 11: 284-290, 2005. [PubMed: 15711558] [Full Text: https://doi.org/10.1038/nm1194]
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Lee, H.-M., Yuk, J.-M., Kim, K.-H., Jang, J., Kang, G., Park, J. B., Son, J.-W., Jo, E.-K. Mycobacterium abscessus activates the NLRP3 inflammasome via dectin-1-Syk and p62/SQSTM1. Immun. Cell Biol. 90: 601-610, 2012. [PubMed: 21876553] [Full Text: https://doi.org/10.1038/icb.2011.72]
Mocsai, A., Zhou, M., Meng, F., Tybulewicz, V. L., Lowell, C. A. Syk is required for integrin signaling in neutrophils. Immunity 16: 547-558, 2002. [PubMed: 11970878] [Full Text: https://doi.org/10.1016/s1074-7613(02)00303-5]
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Zou, W., Kitaura, H., Reeve, J., Long, F., Tybulewicz, V. L. J., Shattil, S. J., Ginsberg, M. H., Ross, F. P., Teitelbaum, S. L. Syk, c-Src, the alpha-v-beta-3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J. Cell Biol. 176: 877-888, 2007. [PubMed: 17353363] [Full Text: https://doi.org/10.1083/jcb.200611083]