Tyrosine phosphorylation in Toll-like receptor signaling

Abstract

There is a wealth of knowledge about how different Ser/Thr protein kinases participate in Toll-like receptor (TLR) signaling. In many cases, we know the identities of the Ser/Thr residues of various components of the TLR-signaling pathways that are phosphorylated, the functional consequences of the phosphorylation and the responsible protein kinases. In contrast, the analysis of Tyr-phosphorylation of TLRs and their signaling proteins is currently incomplete, because several existing analyses are not systematic or they do not rely on robust experimental data. Nevertheless, it is clear that many TLRs require, for signaling, ligand-dependent phosphorylation of specific Tyr residues in their cytoplasmic domains; the list includes TLR2, TLR3, TLR4, TLR5, TLR8 and TLR9. In this article, we discuss the current status of knowledge on the effect of Tyr-phosphorylation of TLRs and their signaling proteins on their biochemical and biological functions, the possible identities of the relevant protein tyrosine kinases (PTKs) and the nature of regulations of PTK-mediated activation of TLR signaling pathways.

Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM

“…Tyrosine phosphorylation results in the recruitment of the phosphorylase kinase, such as Ser/Thr kinase and PI3K, to the signaling complex, a step that is essential for the activation of downstream transcription factors (11). Tyrosine phosphorylation then provides docking sites for other proteins (11). Structural analysis indicates that both TRIF and TRAM TIR domains form a BB-loop-mediated homodimer (30).…”

“…It has been reported that TIRAP underwent tyrosine phosphorylation at the residues within its TIR domain following LPS stimulation, and this modification initiated a con- formational change in the TIR domain of TIRAP (12,13), thereby leading to activation of downstream signals. Tyrosine phosphorylation results in the recruitment of the phosphorylase kinase, such as Ser/Thr kinase and PI3K, to the signaling complex, a step that is essential for the activation of downstream transcription factors (11). Tyrosine phosphorylation then provides docking sites for other proteins (11).…”

“…In the setting of TLR pathways, TLR2, TLR3, TLR4, TLR5, TLR8, and TLR9 undergo tyrosine phosphorylation (11), and mutations of tyrosines within their TIR domains suppress TLRs activation. In addition to the receptors, other components of the PRRs signaling pathways (e.g., the adaptors, also undergo tyrosine phosphorylation upon ligand engagement) (11). Tyrosine phosphorylation of TIRAP is required for the recruitment of MyD88 to TLR2 and TLR4 (12,13).…”

“…Serine phosphorylation of NLRC4 (a cytosolic member of the NOD-like receptor family) is critical for inflammasome activation (10). In the setting of TLR pathways, TLR2, TLR3, TLR4, TLR5, TLR8, and TLR9 undergo tyrosine phosphorylation (11), and mutations of tyrosines within their TIR domains suppress TLRs activation. In addition to the receptors, other components of the PRRs signaling pathways (e.g., the adaptors, also undergo tyrosine phosphorylation upon ligand engagement) (11).…”

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/β Signaling Node Leading to TNF Secretion

“…Notably, TLR4 signaling activated in MCs seems to exclusively depend on the function of the MyD88 adapter, because the expression of elements of the MyD88-independent pathway was not detected in bone marrow-derived MCs (BMMCs) (18,19). The participation of Src family kinases in TLR4 signaling in immune cells was suggested (20), and Lyn kinase was shown to participate in the induction of cytokine synthesis after TLR4 triggering in monocytes (21) and MCs (22,23).…”