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Figure: NF kappa-B signalling

- the size of the proteins are not an indication of the molecular weights or amino acid lengths. - all possible pathways do not necessarily all occur in one cell. - rectangular boxes on TNFR & Tradd represent death domains. - NIK (NF kappa B inducing factor) associates with traf-2 or traf-6 & IKAP, IKK-alpha IKK-beta of IKK complex. - both NIK & MEKK1 can phosphorylate IKK-alpha & IKK-beta. - IKK complex phosphorylates I-kappa-B-alpha or I-kappa-B-beta which targets it for degradation, unmasking the nuclear localization signal in RelA of the NF-kappa-B complex. - I-kappa-B-alpha phosphorylation of S32 & S36 leads to ubiquitination of K21 & K22 leading to degradation [7]. - KBRAS-1 & KBRAS-2 associate with IkB when complexed with NFkB & slow down degradation of IkB. - there is also a separate PMA inducible IKK complex containing IKK-epsilon, but not IKK-alpha, IKK-beta, or IKK-gamma. - T cell receptor also activates the PMA inducible IKK complex. - p38MAPK affects NF kappa B dependent gene transcription through regulating activation of TFIID (TBP) - inhibition of phosphorylation of TFIID (TBP) reduces its binding to the TATA box & interaction with p65 subunit of NF kappa B [6]. - NIK also activates MEK & ERK1/2 which act upstream of & regulate NF kappa B DNA binding activity [8]. - PDGF & PMA can activate NAK/TBK1 which acts upstream of I kappa B [7]. - PDGF through ras & PI3K can activate Akt1 kinase (PKB) which associates with & mediates IKK-alpha phosphorylation at T23 & is necessary for NF kappa B activation by TNF [5,9]. - Akt1 activation of NF kappa B also occurs through transactivation potential of p65 subunit [11]. - in TNF-alpha induced pathways, NF kappa B shows anti-apoptotic activity. - proteolysis of IKK beta by caspase-3 interferred with IKK activation & promotes TNF-alpha apoptosis [10]. - PTEN blocks Akt1 kinase activity & blocks ability of TNF to stimulate transactivation domain of p65 subunit of NF kappa B (probably through blocking Akt1 activity but not affecting IKK degradation of IKB) [11]

References

  1. Stancovski & Baltimore. Cell 91:299-302, 1997
  2. Scheidereit. Nature 395:225-6, 1998
  3. Peters et al. Molecular Cell 5:513-22, 2000
  4. Ryam et al. Nature 404:892-7, 2000
  5. Ozes et al. Nature 401:82-5, 1999
  6. Carter et al. J Biol Chem 274:30858-63, 1999
  7. Peters & Maniatis. Biochimica et Biophysica Acta 1471: M57-M62, 2001
  8. Dhawan & Richmond. JBC in press Dec. 28, 2001
  9. Romashkova & Makarov. Nature 401:86-90, 1999
  10. Tang et al. Molecular Cell *:1005-16, 2001
  11. Mayo et al. JBC Jan 17, 2002

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