Syk tyrosine kinase participates in β₁-integrin signaling and inflammatory responses in airway epithelial cells

Abstract

The protein tyrosine kinase Syk is critically involved in immunoreceptor signaling in hematopoietic cells. Recent studies demonstrate Syk expression in nonhematopoietic cells, including fibroblasts, endothelial cells, hepatocytes, and breast epithelium. However, the role of Syk in these cells is uncertain. We hypothesized that Syk is expressed in respiratory epithelial cells (EC) and that it functions as a signaling molecule involved in inflammatory responses in the epithelium. With the use of immunohistochemistry, Western blot, PCR, and laser scanning confocal microscopy, Syk was detected in human, rat, and mouse bronchial epithelium in situ and in cultured human bronchial EC in primary cells and the cell lines HS-24 and BEAS-2B. Syk-dependent signaling pathways in EC were initiated by engagement of beta1-integrin receptors. Stimulation of beta1-integrin receptors by fibronectin or antibody cross-linking caused redistribution of Syk from a cytoplasmic to plasma membrane localization. In stimulated cells, Syk and beta1-integrin colocalized. In addition, following beta1-integrin receptor engagement, tyrosine phosphorylation of Syk was observed. Expression of the intercellular adhesion molecule-1 (ICAM-1) and production of IL-6, both important molecules in lung inflammation, was downregulated in EC treated with Syk small interfering RNA or Syk inhibitor piceatannol. We propose that Syk is involved in signaling pathways induced by integrin engagement in airway EC. Syk-mediated signaling regulates IL-6 and ICAM-1 expression and may be important in the pathophysiology of lung inflammation.

Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis

“…These results indicate that the redistribution of SYK was induced by the engagement of b1-integrins by fibronectin. Although SYK phosphorylation on Tyr525/526 has been demonstrated to be also induced by stimulation with fibronectin in airway epithelial cells, 13 we could not find induction of SYK phosphorylation at Tyr525/526 after adhesion of HCC cells to fibronectin (Supplementary Figure 6). Other tyrosine sites might be activated by stimulation with fibronectin in HCC cells.…”

“…13 To identify whether the localization of SYK was altered in HCC cells due to the engagement of b1-integrins with fibronectin, SYK-tGFPtransfected Hep3B and Huh7 cells were plated on fibronectin-coated surfaces and subsequently examined by confocal microscopy. After 1 h, the adhesion to fibronectin induced visible cytoplasmic spreading of both Hep3B and Huh7 cells on coverslips.…”

“…Conversely, in epithelial cells, b1 integrin-mediated activation of SYK has been demonstrated. [12][13][14] The activation of b1 integrin by fibronectin or antibody crosslinking leads to the redistribution of SYK from the cytoplasm to the plasma membrane, and the induction of tyrosine phosphorylation by SYK. 13,15 Focal adhesions are specific types of large protein complexes through which the cytoskeleton of a cell interacts with proteins of the extracellular matrix.…”

“…[12][13][14] The activation of b1 integrin by fibronectin or antibody crosslinking leads to the redistribution of SYK from the cytoplasm to the plasma membrane, and the induction of tyrosine phosphorylation by SYK. 13,15 Focal adhesions are specific types of large protein complexes through which the cytoskeleton of a cell interacts with proteins of the extracellular matrix. In breast cancer cells, SYK inhibits cell motility, while promoting the expression of cell adhesion molecules, such as vinculin, 15 E-cadherin, 16 and tensin2.…”

Inhibitory Effects of Syk Transfection on Lung Cancer Cell Invasion

“…Recent evidence demonstrated that it is also expressed by many non-hematopoietic cell types (Hoeler et a1., 2005;Ulanova et a1., 2005) and that it plays a negative role in cancer (Hoellenriegel et al, 2012). A significant drop in its expression was first observed during breast cancer progression, but an anomalous Syk expression has now also been evidenced in many other tumor types.…”