The Physiological functions of IKK-selective substrate identification and their critical roles in diseases

Abstract

The nuclear factor κB (NF-κB) transcription factors exert central hub functions in multiple physiologicalprocesses including immune response, cell survival, proliferation and cytokine production, which hasnaturally become the core of research almost in all aspects of biomedical science over 30 years. Sinceboth the activation and termination of NF-κB pathway are tightly regulated, little alteration can lead toexcessive inflammatory responses and even result in tissue damage and severe diseases. The inhibitor ofnuclear factor kappa-B (IκB) kinase (IKK) complex is the main regulator of the NF-κB signaling pathway,they mediate and deliver signals through phosphorylating certain substrates. In recent years, increasedproteins have been identified to be targeted by IKK members and the particular modification mechanismbecomes clear with the development of detecting techniques and structural biology. In this review, wesummarize the known substrates of IKK family members either relevant or irrelevant to NF-κB signaling,their structures and phosphorylation patterns, and the related physiologic and/or pathologic responses.Understanding the regulation of IKKs on their substrates may be helpful to connect IKKs with specificsignaling pathways or physiological phenomena, and is essential for targeting IKKs in clinical research.