The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation.
Receptor expressed in lymphoid tissues (RELT) is a new member of the TNFR family with little known regarding its signaling. Typically, TNFRs engage TRAFs for activation of NF-kappaB and MAPK cascades. We found that RELT does not use the standard signaling pathways characteristic of other TNFRs. While overexpression of RELT in 293 cells induced p38 and JNK activation, it did not activate NF-kappaB. In addition, no binding of RELT to TRAF1,2,3,5, or 6 was detected. Using a yeast two-hybrid system, we identified a Ste20-related proline-alanine-rich kinase (SPAK) that binds RELT. Disruption of the SPAK binding motif, 349RFRV, in RELT inhibited RELT activation of p38 and JNK. In addition, a kinase-dead SPAK acted as an inhibitor of RELT signaling. Thus, we conclude that RELT does not rely on the canonical TRAF pathways for its function, but instead uses a kinase, SPAK, to mediate p38 and JNK activation.
Polek
Tara C
TC
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Talpaz
Moshe
M
Spivak-Kroizman
Taly
T
D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016328:NF-kappa B; C427545:RELT; D018124:Receptors, Tumor Necrosis Factor; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases