Signal Transduction

Edited by: Paul Smaglik Z. Liu, H. Hsu, D.V. Goeddel, M. Karin, "Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis, while NF-[kappa]B activation prevents cell death," Cell, 87:565-76, 1996. (Cited more than 70 times through November 1997) Comments by Michael Karin, Department of Pharmacology, Program in Biomedical Sciences, School of Medicine, University of California, San Diego SIGNAL DISSECTION: Michael Karin and colleagues picked apart the steps in TNF receptor 1 signaling to reveal three separate but interrelated pathways. Unlike more specialized cytokines, tumor necrosis factor (TNF) initiates a variety of biological responses. Some-like cell proliferation and apoptosis-seem in opposition to each other. But picking apart the steps in the signaling pathway reveals how one receptor can control both. Understanding these steps is especially important because most cells have some sort of a TNF receptor. "We have dissected the components," says Michael Karin, a professor of pharmacology at the University of California, San Diego. "We have shown it is possible to separate them genetically." Karin and colleagues' dissection of the signals initiated by the TNF receptor 1 (TNFR1) revealed three separate responses: apoptosis; the activation of NF-kappa B, a transcription factor that inhibits apoptosis; and the activation of JNK, a protein kinase that does not affect the apoptotic process. The three separate pathways explain how one receptor can lead to multiple responses. The key to that understanding, says Karin, is the role of the protein TRAF2, which binds to the receptor midway through the reaction. That protein mediates the activation of both NF-kappa B and JNK, both of which trigger anti-inflammatory responses. "Downstream of TRAF2, we have shown that there is a fork in the pathway," he notes. That fork's existence allows two complimentary proteins to function independently of each other. The two pathways also play a surprising role in regulating the apoptosis pathway, which veers off earlier in the chain of reactions. "Contrary to what has been suggested, the JNK pathway is not necessary for induction of apoptosis," Karin explains. That finding reveals some of the complexity of the TNFR1 pathway, because the NF-[kappa]B leg acts as a "protection signal" by inhibiting apoptosis, while the JNK leg does not prevent it and under highly specialized situations may facilitate it. Karin theorizes that these three legs somehow balance each other-a necessary role in fine-tuning the body's cells by healing some and destroying others. "The interplay is very important, but we still don't understand all the intricacies," he says. The interest in the paper probably results from TNF's ubiquity, according to Karin. While TNF has been known to be important in regulating anti-inflammatory responses for 20 years, the individual biochemical steps have been poorly understood until a few years ago. Karin credits coauthor David V. Goeddel, CEO of Tularik Inc. in San Francisco, and his colleagues at Tularik with developing that field and filling in some of the downstream reactions (see above Hot Paper). "They've done a great deal to define what proteins are recruited to each of the TNF receptors." This paper ties together several fields: TNF, apoptosis, the regulation of cell death, regulation of transcription, and anti-inflammatory chemicals. The elucidation of the separate pathways also provides some insight into possible drug applications, he adds. For example, drugs that inhibit NF-kappa B could be harmful to normal cells because that would allow apoptosis to go on unchecked, but may facilitate cell killing by anti-cancer drugs. Experiments in animals conducted at the University of North Carolina at Chapel Hill by David Brenner, a professor of medicine, and Al Baldwin, a professor of biochemistry and molecular biology, have since have confirmed that, he notes. "If you inhibit NF- kappa B in vivo, the result is a vast increase in the toxicity of the TNF, due to massive apoptosis in the liver," Karin says. One challenge may be to develop anti-inflammatory agents that do not trigger apoptosis. "Maybe it will be a lot safer to work on inhibitors of the JNK pathway."

Signal Transduction

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