1. NF- κ B Signaling Adam Johnson

2. What is NF- κ B?  Transcription Factor  Dimer of Rel and NF- κ B proteins  RelA  RelB  c-Rel  p50  p52

3. Genes Transcribed  Kappa Light Chains (antibody)  CFB (Complement Factor B)  CD54 (ICAM-1)  LBP (LPS binding)  … Immune response!

4. 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

5. Origin of NF- κ B Gilmore, T., & Wolenski, F. (2012)

6. Pathway Overview Cell Signaling Technology, Inc.

7. 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

8. 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

9. Canonical Pathway Wikimedia Commons (2007)

10. 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

11. Non-canonical Pathway Gilmore (2006)

12. 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

13. 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

14. TRAF3 Silencing Liao, et al (2004)

15. 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.