NFB Signaling Adam Johnson What is NFB Transcription

NF-κB Signaling Adam Johnson

What is NF-κB? �Transcription Factor �Dimer of Rel and NF-κB proteins �Rel. A �Rel. B �c-Rel �p 50 �p 52

Genes Transcribed �Kappa Light Chains (antibody) �CFB (Complement Factor B) �CD 54 (ICAM-1) �LBP (LPS binding) �… Immune response!

Origin of NF-κB �Originally thought to be “new” �Present in arthropods such as Drosophila �Not present in yeast or C. elegans �New research reveals NF- κB present in Capsaspora (possible precursor of multicellular animals) �Lots of untapped knowledge

Origin of NF-κB Gilmore, T. , & Wolenski, F.

Pathway Overview Cell Signaling Technology, Inc.

IκB �In most cells, NF-κB sequestered by IκB �IκBs mask nuclear relocation signal �Phosphorylation of IκB by IKK leads to degradation in proteosome �NF-κB relocates to nucleus in absence of IκB

Regulation of NF-κB �NF-κB is self-regulated by negative feedback �NF-κB transcribes the genes for IκB �Composition of NF-κB dimer determines genes transcribed

Canonical Pathway Wikimedia Commons (2007)

Non-canonical Pathway �Primarily involved in lymphocytes �Instead of IκB, p 52 precursor p 100 part of the dimer �NIK (MAP 3 kinase) activates IKK �IKK causes processing of p 100 to p 52 �NF-κB relocates to nucleus

Non-canonical Pathway Gilmore (2006)

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 TRAF 3 �TRAF 3 induces ubiquitination of NIK �To activate the non-canonical pathway, TRAF 3 must be degraded

TRAF 3 Silencing Liao, et al (2004)

References � Cell Signaling Technology, Inc. (July 2009). NF-κB Signaling. Cell Signaling Technology. Retrieved March 19, 2013, from http: //www. cellsignal. com/reference/pathway/NF_kappa. B. html. � Gilmore, T. (2006). Introduction to NF-κB: players, pathways, perspectives. Oncogene, 25, 6680– 6684. � Gilmore, T. , & Wolenski, F. (2012). NF-κB: 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-κB pathway. Immunological Reviews, 246(1), 125 -140.