Regulation of NF-κB signaling by ASK1 through interaction with NIK

摘要

Apoptosis signal-regulating kinase 1 (ASK 1) is mitogen-activated protein kinase kinase kinase 5 (MAP3K5) that activates the MAP2K-JNK/p38 signal cascades. Overexpressed ASK1 has been reported to induce apoptosis. ASK1 is a serine/ threonine kinase that regulates Fas and tumor necrosis factor-α (TNF-α) pathways. ASK1 is activated by various stresses such as oxidative stress, endoplasmic reticulum (ER) stress, calcium influx, TNF-α, and lipopolysaccharide (LPS). Nuclear factor κ-B (NF-κB) inducing kinase (NIK) is another member of the MAP3K family, which plays a critical role in constitutive activation of NF-κB. NIK phosphorylates and activates inhibitor of NF-κB kinase (IKK)-α/β. Activated IKK-α/β lead to phosphorylation and degradation of inhibitor of NF-κB-α (IkB-α) followed by NF-κB activation. NIK contributes to the cell survival and transformation. Other MAP3Ks, including MEKK3 and TAK1 have been known to activate NF-κB with cellular mechanisms. In addition, ASK1 has been reported to negatively regulate IL-1-induced NF-κB activity through disruption of TRAF6-TAK1 interaction.