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Src Family Kinase Tyrosine Phosphorylates Toll‐like Receptor 4 To Dissociate MyD88 And Mal/Tirap Suppressing LPS Induced Inflammatory Responses
Author(s) -
Rhee Sang Hoon,
Im Eunok,
Mitchell Jonathon,
Kim Su Jin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.806.8
Subject(s) - lyn , src family kinase , proto oncogene tyrosine protein kinase src , tyrosine protein kinase csk , phosphorylation , microbiology and biotechnology , tlr4 , tyrosine kinase , tyrosine phosphorylation , kinase , chemistry , receptor tyrosine kinase , signal transduction , cancer research , biology , sh3 domain
Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll‐like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member‐deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK‐deficient condition. Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS‐induced NFkB and JNK1/2 activation and consequently suppresses LPS‐induced cytokine production. TLR4 normally recruits TIR domain‐containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS‐induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase‐dead SFK‐Lyn (Y397/508F) and constitutively active SFK‐Lyn (Y508F), we found that the kinase‐dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase‐active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4‐SFK interaction. Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS‐induced inflammatory responses, suggesting a negative feedback loop regulated by SFK‐induced tyrosine phosphorylation in TLR4. Support or Funding Information Supported by a grant from Oakland University and the NIH (DK079015, S.H.R) and by Basic Science Research Program through the NRF of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03932222, E.I.) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .