TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40.
Signaling by TNF-family receptor CD40 involves TRAF-family adaptor proteins, leading to activation of protein kinases that induce NFkappaB-family transcription factors. We report here that mitogen activated protein kinase kinase kinase-8 (MAP3K8), Tpl2/COT1, is recruited to the CD40 complex via a mechanism dependent on TRAF-binding sites in CD40. Tpl2/COT1 was shown to participate in CD40 signaling based on the ability of a catalytically inactive mutant to suppress CD40-mediated IkappaB kinase activation and induction of NFkappaB-responsive promoters, without affecting signaling by TNF. Tpl2 (-/-) fibroblasts were also deficient in CD40 but not TNF signaling, further supporting a unique role for Tpl2 in CD40 signaling. Experiments using dominant-negative Tpl2 suggest this kinase functions distal to TRAFs but proximal to the TAK1/TAB1 signaling complex, within the IKK/NFkappaB activation pathway. These results indicate a distinction between TNF Receptor family members CD40 and TNFR1 in their utilization of MAP3Ks, and demonstrate TRAF-dependence of Tpl2 association with the CD40 receptor complex.
Chan
Henry
H
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Reed
John C
JC
D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D019013:CD40 Antigens; D020930:MAP Kinase Kinase Kinases; D011518:Proto-Oncogene Proteins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C069937:MAP3K8 protein, human