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SYK

Official Full Name
spleen associated tyrosine kinase
Organism
Homo sapiens
GeneID
6850
Background
This gene encodes a member of the family of non-receptor type Tyr protein kinases. This protein is widely expressed in hematopoietic cells and is involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. It is thought to be a modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
Synonyms
IMD82; p72-Syk;
Bio Chemical Class
mRNA target
Protein Sequence
MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRKAHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPFEDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQIVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQLVEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPKPGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRPKEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAEANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSMGMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYAPECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPREMYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN
Open
Disease
Eczema, Lymphoma, Solid tumour/cancer
Approved Drug
1 +
Clinical Trial Drug
17 +
Discontinued Drug
2 +

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Detailed Information

SYK (Spleen Tyrosine Kinase) is located on human chromosome 9q22.2 and encodes a non-receptor tyrosine kinase. The protein structure of SYK includes two tandem SH2 domains at the N-terminus and a kinase domain at the C-terminus, making it an essential molecule in immune signal transduction. SYK is expressed broadly in hematopoietic cells such as B cells, macrophages, and platelets, playing a pivotal role in initiating and amplifying immune responses. It mediates downstream signaling by binding to immune receptor tyrosine activation motifs (ITAMs) via its SH2 domains. The activation of SYK is triggered by the phosphorylation of immune receptors such as BCR (B cell receptor), FcR (Fc receptors), or integrin receptors, recruiting adaptor proteins such as VAV, PLCγ, and PI3K to form a complex signaling network that regulates various immune processes.

Figure 1. Role of SYK in key signaling systems involved in the immune system.Figure 1. Role of SYK in key signaling systems involved in the immune system. (Cooper N, et al., 2023)

Biological Functions and Pathological Mechanisms

The central biological function of SYK is its involvement in coordinating both innate and adaptive immune responses. Its role is crucial not only in immunity but also in cellular homeostasis:

In B cells, SYK is an indispensable molecule for BCR signal transduction. It is essential for the differentiation of pre-B cells into mature B cells, playing a critical role in the adaptive immune response. SYK activation regulates the activation of downstream signaling cascades that lead to B cell proliferation, survival, and class-switch recombination.

In macrophages, SYK recognizes pathogen-associated molecular patterns (PAMPs) through receptors such as CLEC7A, triggering oxidative stress (ROS) production and inflammasome activation, which are key mechanisms in the body's innate immune defense against pathogens.

In platelets, SYK integrates signals from collagen receptors (GPVI) to regulate thrombus formation and vascular repair processes. Its role in platelet activation is critical for wound healing and maintaining vascular integrity.

Pathological Mechanisms and Disease Associations

Gain-of-function mutations or abnormal activation of SYK have been linked to several autoimmune diseases and inflammatory disorders:

Very Early Onset Inflammatory Bowel Disease (VEOIBD): A study led by Ying Huang's team at Fudan University identified novel SYK mutations (e.g., p.R551Q) in patients with early-onset, severe inflammatory bowel disease. These mutations cause a multi-organ inflammatory syndrome, with clinical manifestations such as intractable diarrhea, arthritis, and skin rashes starting within two weeks of birth. Mechanistically, the mutation leads to enhanced SYK autophosphorylation, sustained activation of the ERK/JNK pathways, and overproduction of Th1/Th17 cytokines (e.g., IL-17, IFN-γ), resulting in damage to the intestinal epithelial barrier and contributing to the disease pathology.

Autoimmune Diseases: In rheumatoid arthritis (RA), SYK activity is 3–5 times higher in synovial tissues, and the phosphorylation status of SYK correlates directly with the extent of joint destruction. SYK also plays a key role in systemic lupus erythematosus (SLE) by regulating the NF-κB pathway, contributing to the production of autoantibodies that target various tissue components.

Additionally, SYK exhibits a dual role in solid tumors:

In cholangiocarcinoma, its overexpression leads to metastasis by remodeling the actin cytoskeleton, facilitating tumor cell migration and invasion.

In breast cancer, however, SYK appears to have a tumor-suppressive role. Loss of expression due to promoter methylation has been associated with increased tumor invasiveness and poor prognosis.

Targeted Therapeutic Applications

SYK inhibitors have become a major focus in translational research due to their potential in treating both inflammatory diseases and cancer:

Inflammatory Diseases: Fostamatinib, an oral SYK inhibitor, has been approved by the FDA for the treatment of primary immune thrombocytopenia (ITP). Phase III trials demonstrated a sustained response rate of 43%, which is significantly higher than the placebo group's 14%. In Phase II studies for rheumatoid arthritis (RA), the combination of Fostamatinib with methotrexate led to an increase in the ACR50 remission rate to 35%. These studies underscore the potential of SYK inhibition in managing chronic autoimmune and inflammatory diseases.

Cancer Therapy: Entospletinib has shown promising results in treating relapsed/refractory acute myeloid leukemia (AML), with a median survival of 7.9 months in Phase II trials. Preclinical studies in cholangiocarcinoma models also showed that SYK inhibitors, when combined with gemcitabine, significantly reduce lung metastasis by 60%. These findings suggest that SYK inhibition can be an effective strategy for treating both hematologic malignancies and solid tumors.

In the field of gene therapy, CRISPR/Cas9 technology has been applied to correct SYK mutations. For example, Ying Huang's team collaborated with East China Normal University's Li Dali to develop a SYK point mutation mouse model (simulating p.R551Q). Bone marrow transplantation and SYK inhibitor treatments in these models significantly alleviated arthritis phenotypes, providing potential curative strategies for VEOIBD.

Reference

  1. Li M, Wang P, Zou Y, et al. Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases. Heliyon. 2023 Apr 22;9(5):e15625.

  2. Cooper N, Ghanima W, Hill QA, et al. Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib. Platelets. 2023 Dec;34(1):2131751.

  3. Kurniawan DW, Storm G, Prakash J, et al. Role of spleen tyrosine kinase in liver diseases. World J Gastroenterol. 2020 Mar 14;26(10):1005-1019.

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