Etk/BMX, a Btk Family Tyrosine Kinase, and Mal Contribute to the Cross-Talk between MyD88 and FAK Pathways

Abstract

MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin α5β1, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocyte s (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.

The Tyrosine Kinase BMX Is an Essential Mediator of Inflammatory Arthritis in a Kinase-Independent Manner

“…A similar study described in synovial fibroblasts a functional and physical interaction of BMX with MyD88 and Mal, components of the LPS signaling pathway (31). In this case, an siRNA against BMX showed inhibition of LPS-induced IL-6 secretion, very similar to our results.…”

“…It has also been demonstrated that BMX is involved in cardiac hypertrophy induced by pressure overload (27) or VEGF-B (28). Furthermore, a role of BMX in TLR signaling and cytokine secretion has been suggested based on its activation by TLR ligands (29)(30)(31). Finally, skin-specific overexpression of BMX has been shown to generate skin hyperplasia and inflammatory angiogenesis (32).…”

Germinal center kinases in immune regulation

“…[86][87][88] FAK consists of an N-terminal FERM domain, a tyrosine kinase domain, a proline-rich region and a C-terminal FAT domain. The FERM domain interacts with the kinase domain, leading to autoinhibition of FAK.…”

“…89 FAK is involved with TLR-induced MyD88 signaling, which plays a role in initiating innate immune responses. 87 FAK and CD4 have been implicated in a signaling complex in T cells stimulated by the HIV protein gp120. 88 The FAT domain binds to the CD4 endocytosis motif, which limits lymphocyte-specific protein tyrosine kinase binding to CD4.…”

Bruton’s Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes

“…Transient transfection of FLS with Clear-MiR miRNA inhibitor (200 nM) and reporter constructs (200 ng/ml) was performed using the human dermal fibroblast Nucleofector kit from Amaxa as previously described (27). Transient transfection of THP-1 cells with miR-346 mimic (200 nM) was performed using the cell line Nucleofector kit V from Amaxa.…”