NF-κB Signaling Many Roads Lead To Madrid

move into the nucleus is also carried out by the protea-some but only after prior phosphorylation of I␬B by the South San Francisco, California 94080 2 Ontario Cancer Institute I␬B kinase complex (IKK). The IKK is composed of three subunits: two, IKK␣ and IKK␤, are bona fide kinases, 620 University Avenue Toronto, Ontario M5G 2C1 while the third, IKK␥ (NEMO), has no catalytic activity but plays a critical regulatory role. In vitro, both IKK␣ Canada and IKK␤ phosphorylate two specific serine residues within the N terminus of I␬B; however, in vivo, IKK␤ is the predominant I␬B kinase. Phosphorylated I␬B is The involvement of the transcription factor NF-␬B in a plethora of cellular activities has made it one of the recognized by ␤-TrCP, a component of the SCF (skp-1/ Cul/F box) ubiquitin ligase complex that mediates poly-most studied proteins. The emerging understanding of new roles for NF-␬B and complexities of the regula-ubiquitination of I␬B and its subsequent proteasomal degradation (reviewed in Karin and Ben-Neriah, 2000). tion of its function was the focus of a recent Juan March workshop held recently in Madrid, Spain. In contrast, IKK␣ mediates the phosphorylation-dependent processing of p100, resulting in the generation of p52. While the upstream kinase responsible for activa-The NF-␬B family of transcription factors are involved tion of IKK␤ remains unclear, it is evident that NIK (NF-mainly in stress-induced, immune, and inflammatory re-␬B-inducing kinase) activates IKK␣ by phosphorylating sponses. In addition, these molecules play important it within its activation loop, at least in vitro (see Figure 1). roles during the development of certain hemopoietic cells, keratinocytes, and lymphoid organ structures. More recently, NF-␬B family members have been impli-Regulation by Degradation cated in neoplastic progression and the formation of Conventional wisdom holds that a central point of NF-neuronal synapses. These important and diverse func-␬B regulation is the translocation of activated NF-␬B tions make NF-␬B one of the most studied transcrip-from the cytoplasm to the nucleus. Cytoplasmic reten-tional factors in biology. Members of this family are tion of the inactive I␬B/NF-␬B complex is thought to formed by dimeric combinations of subunits and are be due to the masking of the dual nuclear localization activated by a number of receptor-mediated signaling signals (NLS) located on NF-␬B by I␬B. Gourisankar pathways. Once activated, they stimulate the transcrip-Ghosh (San Diego) discussed the need to modify this tion of specific sets of target genes mediating a plethora simplistic model in light …