PYK2 interacts with MyD88 and regulates MyD88-mediated NF-kappaB activation in macrophages.
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-kappaB 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 IkappaB, an inhibitor of NF-kappaB nuclear translocation, and decreased NF-kappaB activation and IL-1beta expression by LPS. These results suggest that via interaction with MyD88, PYK2 is involved in modulating cytokine (e.g., LPS) stimulation of NF-kappaB activity and signaling, providing a mechanism underlying PYK2 regulation of an inflammatory response.
Xi
Cai-Xia
CX
Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Xiong
Fei
F
Zhou
Zheng
Z
Mei
Lin
L
Xiong
Wen-Cheng
WC
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010457:Peptidoglycan / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010457:Peptidoglycan; D051996:Transcription Factor RelA; D051418:Focal Adhesion Kinase 2