Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance.

Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Research Abstract Details 

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Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Abstract Text:

Andrei E Medvedev,Wenji Piao,Joanna Shoenfelt,Sang Hoon Rhee,Haiyan Chen,Subhendu Basu,Larry M Wahl,Matthew J Fenton,Stefanie N Vogel,

In this study, we examined whether tyrosine phosphorylation of the Toll-IL-1 resistance (TIR) domain of Toll-like receptor (TLR) 4 is required for signaling and blocked in endotoxin tolerance. Introduction of the P712H mutation, responsible for lipopolysaccharide (LPS) unresponsiveness of C3H/HeJ mice, into the TIR domain of constitutively active mouse DeltaTLR4 and mutation of the homologous P714 in human CD4-TLR4 rendered them signaling-incompetent and blocked TLR4 tyrosine phosphorylation. Mutations of tyrosine residues Y674A and Y680A within the TIR domains of CD4-TLR4 impaired its ability to elicit phosphorylation of p38 and JNK mitogen-activated protein kinases, IkappaB-alpha degradation, and activation of NF-kappaB and RANTES reporters. Likewise, full-length human TLR4 expressing Y674A or Y680A mutations showed suppressed capacities to mediate LPS-inducible cell activation. Signaling deficiencies of the Y674A and Y680A TLR4s correlated with altered MyD88-TLR4 interactions, increased associations with a short IRAK-1 isoform, and decreased amounts of activated IRAK-1 in complex with TLR4. Pretreatment of human embryonic kidney (HEK) 293/TLR4/MD-2 cells with protein tyrosine kinase or Src kinase inhibitors suppressed LPS-driven TLR4 tyrosine phosphorylation, p38 and NF-kappaB activation. TLR2 and TLR4 agonists induced TLR tyrosine phosphorylation in HEK293 cells overexpressing CD14, MD-2, and TLR4 or TLR2. Induction of endotoxin tolerance in HEK293/TLR4/MD-2 transfectants and in human monocytes markedly suppressed LPS-mediated TLR4 tyrosine phosphorylation and recruitment of Lyn kinase to TLR4, but did not affect TLR4-MD-2 interactions. Thus, our data demonstrate that TLR4 tyrosine phosphorylation is important for signaling and is impaired in endotoxin-tolerant cells, and suggest involvement of Lyn kinase in these processes.

Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Publishing Authors By Initials

AE Medvedev,W Piao,J Shoenfelt,SH Rhee,H Chen,S Basu,LM Wahl,MJ Fenton,SN Vogel,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: src-family kinases research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: src-family kinases research

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MEDLINE DATE:

Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 16042-53

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 28

MONTH: 03

YEAR: 2007

Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Keywords Mesh Terms:

KEYWORDS: src-Family Kinases

MESH TERMS: metabolism

Chemical & Substance for Abstract: Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. Information

Substance Name: p38 Mitogen-Activated Protein Kinases

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance.

AFFILIATION: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. amedvedev@som.umaryland.edu

Country: United States

AGENCY: United States NIAID

GRANT: AI-44936

ACRONYM: AI

MEDLINETA: J Biol Chem

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