PMID:23962979

Citation	Lin, YC, Huang, DY, Chu, CL, Lin, YL and Lin, WW (2013) The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3. Sci Signal 6:ra71
Abstract	Toll-like receptors (TLRs) are a major family of pattern recognition receptors, and they play a crucial role in innate immune responses. Activation of TLR4 signaling at the plasma membrane by its ligand lipopolysaccharide (LPS) stimulates a proinflammatory pathway dependent on the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor-associated factor 6) and the kinase TAK1 (transforming growth factor β-activated kinase 1), whereas TLR4 signaling at endosomes stimulates the production of type I interferons (IFNs) through a pathway that depends on TRAF3 and the kinase TBK1 (TANK-binding kinase-1). We found that the nonreceptor tyrosine kinase Syk partially mediated the endocytosis of TLR4, but it also played a dual role in TLR4-mediated signaling. LPS-dependent stimulation of TLR4 in Syk-deficient macrophages led to enhanced activation of TAK1 and increased production of proinflammatory cytokines compared to that in wild-type macrophages. In contrast, Syk-deficient macrophages exhibited decreased TLR4-dependent activation of TBK1 signaling and production of type I IFNs. We found that Syk was present in both TRAF6- and TRAF3-containing signaling complexes; however, the LPS-dependent, lysine 63-linked ubiquitination of TRAF6 and TRAF3 was oppositely regulated by Syk. We identified the domains of Syk that interacted with TRAF3, TRAF6, TAK1, and TBK1, factors activated by multiple TLRs, which suggests that Syk may act as a common regulator of various TLR responses. Together, our results demonstrate the opposing regulatory roles of Syk in TLR-mediated TRAF6 and TRAF3 signaling pathways, which suggests that Syk may fine-tune the innate immune response to lessen inflammation.
Links	PubMed Online version:10.1126/scisignal.2003973
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:KSYK		GO:0002092: positive regulation of receptor internalization	ECO:0000315:		P		Fig. 1.E and 1.D Internalization of TLR4 by LPS mediated endocytosis via CD14 amounts was increased in presence of Syk compared to mutant.	complete CACAO 8570
MOUSE:KSYK	involved_in	GO:0002092: positive regulation of receptor internalization	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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