Tumor necrosis factor-related apoptosis-inducing ligand receptors signal NF-kappaB and JNK activation and apoptosis through distinct pathways.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that interacts with several receptors, including TRAIL-R1, TRAIL-R2, and TRAIL-R4. TRAIL-R1 and TRAIL-R2 can induce apoptosis of cancer cells and activate the transcription factor NF-kappaB. TRAIL-R4 can activate NF-kappaB and protect cells from TRAIL-induced apoptosis. Here we show that TRAIL-R1-, TRAIL-R2-, and TRAIL-R4-induced NF-kappaB activation are mediated by a TRAF2-NIK-IkappaB kinase alpha/beta signaling cascade but is MEKK1 independent. TRAIL receptors also activate the protein kinase JNK. JNK activation by TRAIL-R1 is mediated by a TRAF2-MEKK1-MKK4 but not the TRAF2-NIK/IkappaB kinase alpha/beta signaling pathway. We also show that activation of NF-kappaB or overexpression of TRAIL-R4 does not protect TRAIL-R1-induced apoptosis. Moreover, inhibition of NF-kappaB by IkappaBalpha sensitizes cells to tumor necrosis factor- but not TRAIL-induced apoptosis. These findings suggest that TRAIL receptors induce apoptosis, NF-kappaB and JNK activation through distinct signaling pathways, and activation of NF-kappaB is not sufficient for protecting cells from TRAIL-induced apoptosis.
Hu
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National Jewish Medical and Research Center, Division of Basic Immunology, Department of Immunology, Denver, Colorado 80206, USA.
Johnson
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Shu
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D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms; D002460:Cell Line; D005260:Female; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases