Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

Abstract

Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

Role of Protein Kinase C<i>δ</i>-Mediated Spleen Tyrosine Kinase (Syk) Phosphorylation on Ser in the Amplification of Oral Mucosal Inflammatory Responses to <i>Porphyromonas gingivalis</i>

“…Since in addition to Syk phosphorylation on Tyr sites, the kinase is also phosphorylated rapidly on Ser residues [19] [22], we next assessed the kinetics of Syk phosphorylation on Ser and Tyr in the acinar cells subjected to P. gingivalis LPS stimulation. The results revealed that the LPS-induced Syk phosphorylation on Ser precedes in time-dependent manner ahead of the kinase phosphorylation on Tyr (Figure 2).…”

“…These data, thus suggest the involvement of the novel PKC isozyme, identified earlier as PKCδ [27], in the processes of salivary gland acinar cell Syk phosphorylation on Ser. As Syk localizes mainly in cytoplasm and its association with the membrane-bound TLR4 complex upon activation requires its membrane recruitment [19], we also examined the effect of P. gingivalis LPS on the requirement …”

“…Indeed, evidence indicates that in response to stimulus, c-Jun, c-Fos, ATF2, and NF-κB factors undergo rapid phosphorylation by the specific upstream kinases that affect significantly their dimerization with different partners of transcription factor family and hence the transcriptional activity of NF-κB and AP1 complex [14] [15] [16]. Moreover, LPS-induced TLR4 activation and the ensuing phosphorylation of its tyrosine domain by Src-family kinases [6] [17], provide a convenient docking site for the recruitment of spleen tyrosine kinase (Syk), the activation of which is known to increase the expression of inflammatory genes [17] [18] [19].…”

“…The first step in Syk activation is its binding through SH2 domains to the intracellular Toll-IL-1 receptor (TIR) domain of TLR4 or signaling proteins containing phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic regions [19]. This results in conformational changes in Syk and its activation through Journal of Biosciences and Medicines phosphorylation on several tyrosine residues, which leads to the activation of the PLC, PI3K, MAPK and ERK signaling cascades, and amplification in the induction of inflammatory response [19] [20].…”

“…Although phosphorylation of Syk on multiple Tyr sites is the most apparent posttranslational modification affecting the kinase signaling potential, there are reports demonstrating that upon stimulation Syk also undergoes rapid phosphorylation on several residues of Ser [19] …”