RESEARCH ARTICLE
Phosphorylated Toll-Like Receptor 2 Interacts with Fyn and Cross-Talks with the Phosphorylation-Independent TLR2-Signaling Pathway
Robert W. Finberg, Ching Yim, Jing Yan, Lu Cheng Cao, Leisa Mandell, Evelyn A. Kurt-Jones*
Article Information
Identifiers and Pagination:
Year: 2012Volume: 5
First Page: 36
Last Page: 45
Publisher Id: TOIJ-5-36
DOI: 10.2174/1874226201205010036
Article History:
Received Date: 16/1/2012Revision Received Date: 2/4/2012
Acceptance Date: 3/4/2012
Electronic publication date: 20/9/2012
Collection year: 2012
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Following ligand stimulation, several Toll-like receptors (TLRs) are phosphorylated at tyrosine residues in their intracellular domains. However, the precise chain of events leading to tyrosine-phosphorylation-dependent TLR-mediated cytokine secretion has not been defined. We focused on elaborating the signaling pathway of tyrosine-phosphorylated TLR2. We demonstrated that two tyrosine residues in the intracellular domain of TLR2, Y616 and Y761, were important for cytokine secretion. We also showed that the src-kinase, Fyn, is constitutively associated with TLR2. TLR2-ligand stimulation increases the amount of phosphorylated Fyn and phosphorylated TLR2. The p85-PI3K complex together with PKCζ associated with TLR2 in a src-kinase dependent manner. We identified crosstalk between this complex and two components of the TLR2 tyrosine-phosphorylation-independent pathway, IRAK-1 and TRAF6. Our results demonstrate that the downstream events of ligand-stimulated TLR2, including activation of NFκB and Erk1/2 as well as cytokine secretion, are src-kinase dependent.
