TY - JOUR
T1 - Functional interactions of transforming growth factor β-activated kinase I with IκB kinases to stimulate NF-κB activation
AU - Sakurai, Hiroaki
AU - Miyoshi, Hidetaka
AU - Toriumi, Wataru
AU - Sugita, Takahisa
PY - 1999/4/9
Y1 - 1999/4/9
N2 - Several mitogen-activated protein kinase kinase kinases play critical roles in nuclear factor-κB (NF-κB) activation. We recently reported that the overexpression of transforming growth factor-β-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, together with its activator TAK1-binding protein 1 (TAB1) stimulates NF-κB activation. Here we investigated the molecular mechanism of TAK1- induced NF-κB activation. Dominant negative mutants of IκB kinase (IKK) α and IKKβ inhibited TAK1-induced NF-κB activation. TAK1 activated IKKα and IKKβ in the presence of TAB1. IKKα and IKKβ were coimmunoprecipitated with TAK1 in the absence of TAB1. TAB1-induced TAK1 activation promoted the dissociation of active forms of IKKα and IKKβ from active TAK1, whereas the IKK mutants remained to interact with active TAK1. Furthermore, tumor necrosis factor-α activated endogenous TAK1, and the kinase-negative TAK1 acted as a dominant negative inhibitor against tumor necrosis factor-α- induced NF-κB activation. These results demonstrated a novel signaling pathway to NF-κB activation through TAK1 in which TAK1 may act as a regulatory kinase of IKKs.
AB - Several mitogen-activated protein kinase kinase kinases play critical roles in nuclear factor-κB (NF-κB) activation. We recently reported that the overexpression of transforming growth factor-β-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, together with its activator TAK1-binding protein 1 (TAB1) stimulates NF-κB activation. Here we investigated the molecular mechanism of TAK1- induced NF-κB activation. Dominant negative mutants of IκB kinase (IKK) α and IKKβ inhibited TAK1-induced NF-κB activation. TAK1 activated IKKα and IKKβ in the presence of TAB1. IKKα and IKKβ were coimmunoprecipitated with TAK1 in the absence of TAB1. TAB1-induced TAK1 activation promoted the dissociation of active forms of IKKα and IKKβ from active TAK1, whereas the IKK mutants remained to interact with active TAK1. Furthermore, tumor necrosis factor-α activated endogenous TAK1, and the kinase-negative TAK1 acted as a dominant negative inhibitor against tumor necrosis factor-α- induced NF-κB activation. These results demonstrated a novel signaling pathway to NF-κB activation through TAK1 in which TAK1 may act as a regulatory kinase of IKKs.
UR - http://www.scopus.com/inward/record.url?scp=0033537866&partnerID=8YFLogxK
U2 - 10.1074/jbc.274.15.10641
DO - 10.1074/jbc.274.15.10641
M3 - 学術論文
C2 - 10187861
AN - SCOPUS:0033537866
SN - 0021-9258
VL - 274
SP - 10641
EP - 10648
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -