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RECEPTORS AND SIGNAL TRANSDUCTION

Selective regulation by -PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils

Department of Pediatrics, University of Pennsylvania School of Medicine, and the Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Submitted 5 November 2003 ; accepted in final form 19 April 2004

TNF is implicated in the attenuation of neutrophil constitutive apoptosis during sepsis. Antiapoptotic signaling is mediated principally through the TNF receptor-1 (TNFR-1). In adherent neutrophils, when -integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling. Previously, we identified the -PKC isotype and phosphatidylinositol (PI) 3-kinase as critical regulators of TNF signaling in adherent neutrophils. Both kinases associate with TNFR-1 in response to TNF and are required for TNFR-1 serine phosphorylation, NF-B activation, and inhibition of apoptosis. The purpose of this study was to examine the role of -PKC and PI 3-kinase in the assembly of TNFR-1 signaling complex that regulates NF-B activation and antiapoptotic signaling. Coimmunoprecipitation studies established that PI 3-kinase, -PKC, and TNFR-1 formed a signal complex in response to TNF. -PKC recruitment required both -PKC and PI 3-kinase activity, whereas PI 3-kinase recruitment was -PKC independent, suggesting that PI 3-kinase acts upstream of -PKC. An important regulatory step in control of antiapoptotic signaling is the assembly of the TNFR-1-TNFR-1-associated death domain protein (TRADD)-TNFR-associated factor 2 (TRAF2)-receptor interacting protein (RIP) complex that controls NF-B activation. Inhibition of either -PKC or PI 3-kinase decreased TNF-mediated recruitment of RIP and TRAF2 to TNFR-1. In contrast, TRADD recruitment was enhanced. Thus -PKC and PI 3-kinase are positive regulators of TNF-mediated association of TRAF2 and RIP with TNFR-1. Conversely, these kinases are negative regulators of TRADD association. These results suggest that -PKC and PI 3-kinase regulate TNF antiapoptotic signaling at the level of the TNFR-1 through control of assembly of a TNFR-1-TRADD-RIP-TRAF2 complex.

inflammation; tumor necrosis factor receptor-1-associated death domain protein; receptor interacting protein; tumor necrosis factor receptor-associated factor 2; antiapoptotic signaling

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