Regulated commitment of TNF receptor signaling: A molecular switch for death or activation

Tumor necrosis factor receptor (TNFR) superfamily members can induce a cont ext-dependent apoptosis or cell activation. However, the mechanisms by whic h these opposing programs are selected remain unclear. We show that in T ce lls, TNFR2 (TNFRSF1B) signaling is dramatically affected by the intracellul ar mediator RIP, a protein Ser/Thr kinase required for NF-kappa B activatio n by TNFR1 (TNFRSF1A). In the presence of RIP, TNFRP triggers cell death, w hereas in the absence of RIP, TNFR2 activates NF-kappa B. RIP is induced du ring IL2-driven T cell proliferation, and its inhibition reduces susceptibi lity to TNF-dependent apoptosis. Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 an d TNFRP as apoptotic mediators.