TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway.
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor kappaB (NF-kappaB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-kappaB activator (TANK), in TRAF2-mediated NF-kappaB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-kappaB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.
Chin
A I
AI
Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California Los Angeles, 90095, USA.
Shu
J
J
Shan Shi
C
C
Yao
Z
Z
Kehrl
J H
JH
Cheng
G
G
D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D004789:Enzyme Activation; D018858:Germinal Center / Q000166:cytology; D000081410:Germinal Center Kinases; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014066:Palatine Tonsil / Q000166:cytology; D010446:Peptide Fragments / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6
D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D000081410:Germinal Center Kinases; D010446:Peptide Fragments; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; C484406:TANK protein, human; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases