MADD, a Novel Death Domain Protein That Interacts with the Type 1 Tumor Necrosis Factor Receptor and Activates Mitogen-activated Protein Kinase

doi:10.1074/jbc.272.18.12069

MADD, a Novel Death Domain Protein That Interacts with the Type 1 Tumor Necrosis Factor Receptor and Activates Mitogen-activated Protein Kinase*

From the Small Molecule Drug Discovery Group, Genetics Institute, Inc., Cambridge, Massachusetts 02140

Abstract

The death domain of the type 1 tumor necrosis factor receptor (TNFR1) mediates interactions with several proteins involved in signaling the downstream effects of TNF. We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR1 through its own C-terminal death domain. MADD interacts with TNFR1 residues that are critical for signal generation and coimmunoprecipitates with TNFR1, implicating MADD as a component of the TNFR1 signaling complex. Importantly, we have found that overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK), and expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A₂. These data indicate that MADD links TNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) U77352 .
↵‡ To whom correspondence should be addressed: 87 CambridgePark Dr., Genetics Institute, Inc., Cambridge, MA 02140. Tel.: 617-498-8934; Fax: 617-498-8993.
↵1 The abbreviations used are: TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor type 1; MAP kinase, mitogen-activated protein kinase; cPLA₂, cytosolic phospholipase A₂; PCR, polymerase chain reaction; GST, glutathione S-transferase; MBP, maltose binding protein; HA, hemagglutinin; ERK, extracellular signal-regulated kinase; JNK, c-JUN N-terminal kinase.
↵2 A. R. Schievella and L.-L. Lin, unpublished data.
- Received November 26, 1996.
- Revision received February 18, 1997.