| First Author | Dammann K | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1853 |
| Issue | 10 Pt A | Pages | 2349-60 |
| PubMed ID | 26036343 | Mgi Jnum | J:233928 |
| Mgi Id | MGI:5788385 | Doi | 10.1016/j.bbamcr.2015.05.031 |
| Citation | Dammann K, et al. (2015) PAK1 modulates a PPARgamma/NF-kappaB cascade in intestinal inflammation. Biochim Biophys Acta 1853(10 Pt A):2349-60 |
| abstractText | P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFalpha injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFalpha. NF-kappaB and PPARgamma were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNgamma, IL-1beta, and TNFalpha. In vivo, mice administered with TNFalpha showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-kappaB activation. p65 nuclear translocation downstream of TNFalpha was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-kappaB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARgamma and mesalamine recovered PPARgamma through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-kappaB, which was recovered using BADGE, a PPARgamma antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-kappaB activity via suppression of PPARgamma in intestinal epithelial cells. |
