MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase.
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.
Schievella
A R
AR
Small Molecule Drug Discovery Group, Genetics Institute, Inc., Cambridge, Massachusetts 02140, USA.
Chen
J H
JH
Graham
J R
JR
Lin
L L
LL
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D017931:DNA Primers; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation; D005260:Female; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000737:chemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D047990:TNF Receptor-Associated Factor 1; D014158:Transcription, Genetic
D015703:Antigens, CD; D002352:Carrier Proteins; D017931:DNA Primers; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D011506:Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D047990:TNF Receptor-Associated Factor 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases