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Modulation of TLR signalling by the C‐terminal Src kinase (Csk) in macrophages
Author(s) -
Aki Daisuke,
Mashima Ryuichi,
Saeki Kazuko,
Minoda Yasumasa,
Yamauchi Moriyasu,
Yoshimura Akihiko
Publication year - 2005
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2005.00839.x
Subject(s) - tyrosine protein kinase csk , proto oncogene tyrosine protein kinase src , biology , microbiology and biotechnology , sh3 domain , tyrosine kinase , kinase , p38 mitogen activated protein kinases , tyrosine phosphorylation , gene knockdown , phosphorylation , sh2 domain , signal transduction , mapk/erk pathway , biochemistry , apoptosis
In macrophages and monocytes, lipopolysaccharide (LPS) triggers the production of pro‐inflammatory cytokine through Toll‐like receptor (TLR) 4. Although major TLR signalling pathways are mediated by serine or threonine kinases including IKK, TAK1, p38 and JNKs, a number of reports suggested that tyrosine phosphorylation of intracellular proteins is involved in LPS signalling. Here, we identified several tyrosine‐phosphorylated proteins using mass spectrometric analysis in response to LPS stimulation. Among these proteins, we characterized C‐terminal Src kinase (Csk), which negatively regulates Src‐like kinases in RAW 264.7 cells using RNAi knockdown technology. Unexpectedly, LPS‐induced CD40 activation and the secretion of pro‐inflammatory cytokine such as IL‐6 and TNF‐α, was down‐regulated in Csk knockdown cells. Furthermore, overall cellular tyrosine phosphorylation and TLR4‐mediated activation of IκB‐α, Erk and p38 but not of JNK, were also down‐regulated in Csk knockdown cells. The protein expression levels of a tyrosine kinase, Fgr, were reduced in Csk knockdown cells, suggesting that Csk is a critical regulator of TLR4‐mediated signalling by modifying the levels of Src‐like kinases.