Implication of TNF receptor-I-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation in growth of AIDS-associated Kaposi's sarcoma cells: a possible role of a novel death domain protein MADD in TNF-alpha-induced ERK1/2 activation in Kaposi's sarcoma cells.
TNF-alpha is a key pathogenic mediator of infectious and inflammatory diseases. HIV infection stimulates and dysregulates the immune system, leading to abnormal production of TNF-alpha. Despite its cytotoxic effect on some tumor cell lines, TNF-alpha functions as a growth stimulator for Kaposi's sarcoma (KS), a common malignancy in HIV-infected patients. However, signaling pathways linked to TNF-alpha-induced mitogenic responses are not well understood. We found that extracellular signal-regulated kinases 1 and 2 (ERK1/2) in KS cells were significantly activated by TNF-alpha through tyrosine/threonine phosphorylation. Using neutralizing anti-TNFR-I and TNFR-II mAbs, we have now obtained evidence that TNF-alpha-induced KS cell growth and ERK1/2 activation are mediated exclusively by TNFR-I, not by TNFR-II. A selective inhibitor for ERK1/2 activator kinases, PD98059, profoundly inhibited not only the activation of ERK1/2, but also the TNF-alpha-induced KS cell proliferation. We therefore propose that the TNFR-I-ERK1/2 pathway plays a pivotal role in transmitting to KS cells the mitogenic signals of TNF-alpha. TNFR-I possesses no intrinsic kinase activity, suggesting that TNFR-I-associated proteins may provide a link between TNFR-I and ERK1/2 activation. We found that actinomycin D treatment of KS cells selectively abolished expression of mitogen-activated protein kinase-activating death domain protein (MADD), a novel TNFR-I-associated death domain protein. TNF-alpha failed to induce ERK1/2 activation in the actinomycin D-treated cells. MADD may couple TNFR-I with the ERK1/2 signaling pathway required for KS cell proliferation.
Murakami-Mori
K
K
Department of Microbiology and Immunology, University of California, School of Medicine, Los Angeles 90095, USA.
Mori
S
S
Bonavida
B
B
Nakamura
S
S
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D003609:Dactinomycin / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D013912:Threonine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D006133:Growth Substances; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D013912:Threonine; D014443:Tyrosine; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one