Limited activation interdependence and differing patterns of the in vivo effects of IKK1 and IKK2 downstream of NIK

The protein kinase NIK controls numerous immune functions by signaling for the processing of NF-κB2 and for the activation of other nuclear factor (NF)-κB proteins. NIK associates with IKK1 and has been suggested to exert all its effects via IKK1 activation. In this study, we demonstrate that NIK, by binding to IKK1, also associates with IKK2 and NEMO, allowing NIK to dictate the phosphorylation of IKK2 independently of IKK1's enzymatic function. IKK2 activation is also maintained when the phosphorylation of NF-κB2 is compromised by a mutation of NIK that affects its interaction with IKK1 and NF-κB2. Analyzing mice with this mutation reveals the differing dependencies of various effects of NIK on the activation of IKK1 or IKK2 and on the activation of differing NF-κB proteins. These findings indicate that NIK's signaling mechanisms for the activation of different NF-κB proteins by the two IKKs are not strictly coupled.