Origin of NF- κ B Originally thought to be “new” Present in arthropods such as Drosophila Not present in yeast or C. elegans New research reveals NF- κ B present in Capsaspora (possible precursor of multicellular animals) Lots of untapped knowledge
Origin of NF- κ B Gilmore, T., & Wolenski, F. (2012)
Pathway Overview Cell Signaling Technology, Inc.
IκBIκB In most cells, NF- κ B sequestered by I κ B I κ Bs mask nuclear relocation signal Phosphorylation of I κ B by IKK leads to degradation in proteosome NF- κ B relocates to nucleus in absence of I κ B
Regulation of NF- κ B NF- κ B is self-regulated by negative feedback NF- κ B transcribes the genes for I κ B Composition of NF- κ B dimer determines genes transcribed
Non-canonical Pathway Primarily involved in lymphocytes Instead of I κ B, p52 precursor p100 part of the dimer NIK (MAP3 kinase) activates IKK IKK causes processing of p100 to p52 NF- κ B relocates to nucleus
NIK and Cross-Talk Small concentrations of NIK highly activate the non-canonical pathway NIK activates canonical pathway at high concentrations High levels of activation of both pathways lead to myeloma and lymphoma
NIK Regulation Activated IKK targets NIK for degradation NIK quickly bound by TRAF3 TRAF3 induces ubiquitination of NIK To activate the non-canonical pathway, TRAF3 must be degraded
References Cell Signaling Technology, Inc. (July 2009). NF- κ B Signaling. Cell Signaling Technology. Retrieved March 19, 2013, from http://www.cellsignal.com/reference/pathway/NF_kappaB.html. Gilmore, T. (2006). Introduction to NF- κ B: players, pathways, perspectives. Oncogene, 25, 6680–6684. Gilmore, T., & Wolenski, F. (2012). NF- κ B: where did it come from and why?. Immunological Reviews, 246(1), 14-35. Liao, G.; Zhang M.; Harhaj E.; et al. (2004). Regulation of the NF-kappa B-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. Journal of Biological Chemistry, 279(25), 26243-26250. Sun, S. (2012). The noncanonical NF- κ B pathway. Immunological Reviews, 246(1), 125-140.