Abstract 815: The role of spleen tyrosine kinase (SYK) in paclitaxel resistant ovarian cancer

2012 ◽  
Author(s):  
Stephanie Gaillard ◽  
Alexander Stoeck ◽  
Ben Davidson ◽  
Tian-Li Wang ◽  
Ie-Ming Shih
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Spleen Tyrosine Kinase

scholarly journals Spleen Tyrosine Kinase Inhibition Modulates p53 Activity

2017 ◽  
Vol 10 ◽  
pp. 117906601773156 ◽  
Author(s):  
Mohammad Althubiti
Keyword(s):  
Tyrosine Kinase ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Ht1080 Cell ◽  
P53 Expression ◽  
Chemical Inhibitors ◽  
Dependent Mechanism

Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.

scholarly journals P2-159: DECIPHERING THE ROLE OF SPLEEN TYROSINE KINASE AS A KEY MEDIATOR OF AMYLOID-B CLEARANCE BY MICROGLIA

2019 ◽  
Vol 15 ◽  
pp. P637-P637
Author(s):  
Siok Lam Lim ◽  
Heng Wei Hsu ◽  
Jason Kilian ◽  
Masashi Kitazawa
Keyword(s):  
Tyrosine Kinase ◽  
Spleen Tyrosine Kinase

scholarly journals Role of spleen tyrosine kinase in liver diseases

2020 ◽  
Vol 26 (10) ◽  
pp. 1005-1019 ◽  
Author(s):  
Dhadhang Wahyu Kurniawan ◽  
Gert Storm ◽  
Jai Prakash ◽  
Ruchi Bansal
Keyword(s):  
Tyrosine Kinase ◽  
Liver Diseases ◽  
Spleen Tyrosine Kinase

Abstract 189: The Role of Spleen Tyrosine Kinase, Syk, in CD36-Toll Like Receptor Cooperative Signaling in Atherosclerosis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Tathagat Dutta Ray ◽  
Bhama Ramkhelawon ◽  
Kathryn J Moore
Keyword(s):  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Oxidized Ldl ◽  
Density Lipoprotein ◽  
Sh2 Domain ◽  
Sterile Inflammation ◽  
Toll Like Receptor ◽  
Spleen Tyrosine Kinase

Atherosclerosis is characterized by chronic sterile inflammation of the artery wall in which cells of the monocyte lineage accumulate in response to the deposition of low density lipoprotein (LDL). We previously established that recognition of oxidized LDL (oxLDL) by CD36 triggers assembly of a novel Toll-like receptor heterodimer composed of TLR4 and TLR6. Here we set out to understand the molecular mechanisms of CD36/TLR4/TLR6 activation and establish how it triggers downstream signals that lead to the expression of the pro-inflammatory mediators that have been directly implicated in the deleterious effects of oxLDL and atherosclerosis progression. By confocal microscopy we demonstrate that oxLDL induces CD36, TLR4 and TLR6 co-localization in intracellular compartments, but not on the cell surface of macrophages. Notably, inhibition of oxLDL endocytosis (with Dynasore) or lysosomal maturation (with Bafilomycin A or NH4Cl) blocks CD36-TLR4-TLR6 complex formation and oxLDL-induced cytokine responses in macrophages. These data indicate that both ligand internalization and lysosomal acidification are required for assembly of a functional CD36/TLR4/TLR6 signaling complex. Notably, CD36 contains a hemi-ITIM motif in the C-terminus that is reported to interact with the spleen tyrosine kinase Syk through its SH2 domain. As Syk has recently been implicated in the trafficking of CD14 and TLR4 to the endosome in response to LPS, we investigated the role of this kinase in CD36/TLR4/TLR6 signaling. We find that Syk is required for CD36 internalization and TLR4/TLR6 heterodimerization. Using a pharmacological inhibitor, we show that inhibition of Syk activity blocks oxLDL-induced TLR4-TLR6 co-precipitation and abrogates macrophage expression of both MyD88- (IL-1b, CXCL1) and TRIF-dependent (CCL5) cytokines/chemokines. Together, our data are consistent with a key role for Syk in the trafficking of CD36 and oxLDL to the lysosome, where it coordinates the assembly of a functional TLR4-TLR6 heterodimer to initiate signaling. This model highlights the importance of CD36 as a co-receptor that orchestrates TLR4-TLR6 trafficking and assembly to initiate the detrimental inflammatory responses that promote the progression of atherosclerosis.

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