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...

A defect in regulation of a chloride channel appears to be the molecular basis for cystic fibrosis (CF), a common lethal genetic disease. It is shown here that a chloride channel with kinetic and regulatory properties similar to those described for secretory epithelial cells is present in both T and B lymphocyte cell lines. The regulation of the channels by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase in transformed B cells from CF patients is defective. Thus, lymphocytes may be an accessible source of CF tissue for study of this defect, for cloning of the chloride channel complex, and for diagnosis of the disease.

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Although technological diversification is an important strategic decision for both large and small firms alike, the conventional method of measuring such diversification may well introduce significant scale bias against small-and medium-sized firms. We examine this issue in this study using a sample of 73 Taiwanese integrated-circuit (IC) design firms covering the period from 1995 to 2007 and conclude that the conventional measure of technological diversification reflects the spread or distribution amongst technology classes of a company's current technology portfolio, and does not capture the incremental expansion in technological scope, or the 'dynamic act of diversification', as reflected in our alternative scope measure. Our results suggest clear constraints on the applications made under the conventional index, particularly for firms with small patent scale.

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