TY - JOUR
T1 - TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation
AU - Blonska, Marzenna
AU - Shambharkar, Prashant B.
AU - Kobayashi, Masayuki
AU - Zhang, Dongyu
AU - Sakurai, Hiroaki
AU - Su, Bang
AU - Lin, Xin
PY - 2005/12/30
Y1 - 2005/12/30
N2 - Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-α (TNF-α)-induced IκB kinase (IKK) activation and subsequent activation of transcription factor NF-κB. However, the molecular mechanism by which RIP mediates TNF-α-induced NF-κB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-α receptor complex in a RIP-dependent manner following the stimulation of TNF-α receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-α-induced NF-κB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling.
AB - Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-α (TNF-α)-induced IκB kinase (IKK) activation and subsequent activation of transcription factor NF-κB. However, the molecular mechanism by which RIP mediates TNF-α-induced NF-κB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-α receptor complex in a RIP-dependent manner following the stimulation of TNF-α receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-α-induced NF-κB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling.
UR - http://www.scopus.com/inward/record.url?scp=30044449755&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30044449755&partnerID=8YFLogxK
U2 - 10.1074/jbc.M507807200
DO - 10.1074/jbc.M507807200
M3 - Article
C2 - 16260783
AN - SCOPUS:30044449755
SN - 0021-9258
VL - 280
SP - 43056
EP - 43063
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -