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

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 A 2 . 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. Tumor necrosis factor (TNF)1 is a central player in the regulation of immune responses. Produced mainly by activated macrophages, TNF promotes a wide variety of cellular activities, including the initiation of inflammation, the induction of antiviral responses, and apoptosis. Two receptors for TNF have been cloned, both of which belong to a superfamily of cell surface receptors that includes the Fas antigen and CD40 (1). The TNF receptors share 30% homology in their extracellular domains but are unrelated in their intracellular domains. The intracellular domains of the Fas antigen and the 55-kDa TNF receptor (TNFR1), both of which can trigger apoptosis, share approximately 28% identity in a region known as the death domain (2, 3). This region of TNFR1 has been shown to be necessary and sufficient for signaling cytotoxicity (3, 4).TNFR1 mediates most of the biological effects of TNF (3, 5-8). Engagement of this receptor activates a diverse group of intracellular signaling pathways. Among the early downstream effects of TNF are the activation of kinases, including members of the MAP kinase family (9 -14), and phospholipases, including cytosolic phospholipase A 2 (cPLA 2 ) (reviewed in Ref. 15). The activation of cPLA 2 results in the release of arachidonic acid, which is metabolized into the potent proinflammatory mediators prostaglandins and leukotrienes. TNF also activates several transcription factors, including NF-B and c-JUN/AP-1, leading to the up-regulation of a large number of genes involved in the inflammatory response (16). The signaling elements involved in initiating these pathways were not discovered until recently, when the yeast two-hybrid system was used to identify proteins that associate directly with TNFR1. Briefly, TRADD (17) is a death domain-containing protein that interacts directly with the death domain of TNFR1. TRADD is believed to act as an adaptor protein that recruits two other proteins, TRAF2 and RIP, to the receptor (18, 19). TRAF2 has been implicated in the pathway leading to the activation...

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

“…Both TNFRI and TNFRII have been shown to be involved in cPLA 2 activation. A novel death domain protein, MADD, was shown to interact with TNFRI leading to activation of ERK and c-Jun causing the phosphorylation of cPLA 2 (38). TNFRII, however, was shown to activate cPLA 2 by translocating it to the plasma membrane leading to a calcium efflux rather than through a MAPK-dependent mechanism (24).…”

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

“…The IG20 (Insulinoma-Glucagonoma) is one such gene that can encode at least four different splice variants (SVs), namely IG20pa (i.e., IG20 proapoptotic), MADD/ DENN, IG20-SV2 and DENN-SV (Goto et al, 1992;Lee, 1996, 1998;Cunningham, 1996;Schievella et al, 1997;Al-Zoubi et al, 2001). These four IG20-SVs are distinguished by differential splicing of exons 13L and 16.…”

“…The IG20 gene plays an important role in cancer cell proliferation, apoptosis and survival Lee, 1996, 1998;Schievella et al, 1997;Brinkman et al, 1999;Murakami-Mori et al, 1999;Telliez et al, 2000;AlZoubi et al, 2001;Lim and Chow, 2002;Efimova et al, 2003Efimova et al, , 2004Lim et al, 2004;Ramaswamy et al, 2004). Additionally, it plays an important role in neurotransmission (Zhang et al, 1998;Tanaka et al, 2001;Yamaguchi et al, 2002), neurodegeneration (Del Villar and Miller, 2004) and guanine nucleotide exchange (Wada et al, 1997;Brown and Howe, 1998;Iwasaki and Toyonaga, 2000;Levivier et al, 2001).…”

Tumor necrosis factor signaling

“…182 A protein containing a domain with low DD homology termed MADD or Rab3-GAP binds to the DD of TNF-R1 and is able to activate MAP kinase pathways. 183,184 Various splice variants of MADD exist which are also termed DENN. 185 Further, the adapter protein Grb2 binds to a PLAP motif of TNF-R1, thereby potentially linking this receptor via SOS to Ras, c-Raf and the ERKs.…”