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Volume 271, Number 45, Issue of November 8, 1996 pp. 28097-28104
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Tumor Necrosis Factor Receptors (Tnfr) in Mouse Fibroblasts Deficient in Tnfr1 or Tnfr2 are Signaling Competent and Activate the Mitogen-activated Protein Kinase Pathway with Differential Kinetics

(Received for publication, April 17, 1996, and in revised form, July 29, 1996)

Alexandra Kalb , Horst Bluethmann ^§ , Mark W. Moore ^¶ and Werner Lesslauer

From the  Department of Nervous System Diseases PRPN and the ^§ Department of Gene Technologies PRPG, F. Hoffmann-La Roche, 4070 Basel,  Switzerland and the ^¶ Department of Immunology, Genentech, Inc., South San Francisco,California 94080

To dissect tumor necrosis factor receptor (Tnfr)-1 (CD120a) and Tnfr2 (CD120b)-dependent signal transduction pathways, primary fibroblasts isolated from inguinal adipose tissue of wild type (wt), tnfr1^o, tnfr2^o, and tnfr1^o/tnfr2^o mice were studied. The mitogen-activated protein kinases Erk1 and Erk2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt, tnfr1^o, and tnfr2^o fibroblasts; the activation was down-regulated 60 min after the start of steady state Tnf treatment. Distinct kinetics of Erk1 and Erk2 activation were detected; the Tnfr1-mediated activation of Erk1 and Erk2 started more slowly and persisted for more prolonged times as compared with Tnfr2 activation. Raf-1, Raf-B, Mek-1, Mek kinase, and p90^rsk kinases were also shown to be activated independently in a distinct time-dependent pattern through the two Tnf receptors. In addition, both Tnfr1 and Tnfr2 mediated independently the activation of the transcription factor Ap-1 albeit with parallel activation kinetics. In contrast, Tnfr1 exclusively mediated activation of NF-B and fibroblast proliferation; however, Tnfr2 enhanced proliferation triggered through Tnfr1. These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors.

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