Fig. 5.

PAK1 modulates a PPARγ/p65 cascade. (Left) Within normal differentiated IEC, PAK1 activity and expression is low while PPARγ is present in both the cytoplasm and nucleus. Cytoplasmic NF-kB is maintained in an inactive state via the sequestration of p65 by IkB. PPARγ further regulates free p65 through E3 ligase activity and proteasomal degradation in the cytoplasm. (Middle) In chronic inflammation and colitis associated cancer (CAC) PAK1 is hyperactivated while PPARγ is downregulated. Pro-inflammatory cytokines such as TNFα induce PAK1 phosphorylation, activation, and nuclear colocalization with p65. Activated PAK1 also blocks PPARγ, further increasing the nuclear accumulation of p65 independently of IkB. (Right) The anti-inflammatory drug 5-ASA inhibits PAK1 thereby restoring PPARγ expression, and increasing its activity in inhibiting free p65 in the cytoplasm.