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*
University of Massachusetts Medical School, 364 Plantation St. LRB 226, Worcester, MA 01605, USA.


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© 2011 Finberg et al;

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.

* Address correspondence to this author at the University of Massachusetts Medical School, 364 Plantation St. LRB 226, Worcester, MA 01605, USA; Tel: 508-856-3531; Fax: 508-856-6176; E-mail: evelyn.kurt-jones@umassmed.edu


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.

Keywords: CD14, Fyn, H. pylori, IRAK-1, TIR domain, TLR2, TRAF6.