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From the Klinikum der Universität Ulm, Ulm, 89081 Germany; and the Institut für Experimentelle Onkologie und Therapieforschung der Technischen Universität München, 81675 München, Germany

Tumor necrosis factor (TNF-) is a proinflammatory cytokine. Its pleiotropic biological properties are signaled through two distinct cell surface receptors: the TNF receptor type I (TNFR-I) and the TNF receptor type II. Neither of the two receptors possesses tyrosine kinase activity. A large majority of TNF-–dependent activities can be mediated by TNFR-I. Recently, c-Raf-1 kinase was identified as an intracellular target of a signal transduction cascade initiated by binding of TNF- to TNFR-I. However, the mechanism engaged in TNF-–dependent activation of c-Raf-1 kinase is still enigmatic.

Here we report that the cytosolic adapter protein Grb2 is a novel binding partner of TNFR-I. Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and with its NH₂-terminal SH3 domain to SOS (son of sevenless). A PLAP deletion mutant of TNFR-I fails to bind Grb2. The TNFR-I/Grb2 interaction is essential for the TNF-–dependent activation of c-Raf-1 kinase; activation of c-Raf-1 kinase by TNF- can be blocked by coexpression of Grb2 mutants harboring inactivating point mutations in the NH₂- or COOH-terminal SH3 domain, cell-permeable peptides that disrupt the Grb2/TNFR-I interaction or transdominant negative Ras. Functionality of the TNFR-I/Grb2/SOS/Ras interaction is a prerequisite but not sufficient for TNF-–dependent activation of c-Raf-1 kinase. Inhibition of the TNFR-I/FAN (factor associated with neutral sphingomyelinase) interaction, which is essential for TNF-–dependent activation of the neutral sphingomyelinase, either by cell-permeable peptides or by deletion of the FAN binding domain, prevents activation of c-Raf-1 kinase. In conclusion, binding of the Grb2 adapter protein via its COOH-terminal SH3 domain to the nontyrosine kinase receptor TNFR-I results in activation of a signaling cascade known so far to be initiated, in the case of the tyrosine kinase receptors, by binding of the SH2 domain of Grb2 to phosphotyrosine.

Key Words: Grb2 • tumor necrosis factor • signal transduction • cell-permeable peptides • yeast two-hybrid system

Abbreviations used: aa, amino acid; AP-1, activator protein 1; CAP, ceramide-activated protein; CAT, chloramphenicol acetyltransferase; EGF, epidermal growth factor; n, neutral; NTA, nitrilotriacetic acid; Smase, sphingomyelinase; SOS, son of sevenless.

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