PYK2 interacts with MyD88 and regulates MyD88-mediated NF-κB activation in macrophages

Abstract PYK2 regulates inflammation by modulating MyD88 signaling. PYK2, a major cell adhesion-activated tyrosine kinase, is highly expressed in macrophages and implicated in macrophage activation and inflammatory response. However, mechanisms by which PYK2 regulates inflammatory response are beginning to be understood. In this study, we demonstrate that PYK2 interacts with MyD88, a crucial signaling adaptor protein in LPS and PGN-induced NF-κB activation, in vitro and in macrophages. This interaction, increased in macrophages, stimulated by LPS, requires the death domain of MyD88. PYK2-deficient macrophages exhibit reduced phosphorylation and degradation of IκB, an inhibitor of NF-κB nuclear translocation, and decreased NF-κB activation and IL-1β expression by LPS. These results suggest that via interaction with MyD88, PYK2 is involved in modulating cytokine (e.g., LPS) stimulation of NF-κB activity and signaling, providing a mechanism underlying PYK2 regulation of an inflammatory response.