Crosstalk between Wnt/β-Catenin and NF-κB Signaling Pathway during Inflammation

Abstract

Besides its important role in embryonic development and homeostatic self-renewal in adult tissues, Wnt/β-catenin signaling exerts both anti-inflammatory and proinflammatory functions. This is, at least partially, due to either repressing or enhancing the NF-κB pathway. Similarly, the NF-κB pathway either positively or negatively regulates Wnt/β-catenin signaling. Different components of the two pathways are involved in this crosstalk, forming a complex regulatory network. This review summarizes our current understanding of the molecular mechanisms underlying the cross-regulation between the two pathways and discusses their involvement in inflammation and inflammation-associated diseases such as cancer.

Keywords: NF-κB; Wnt; gene expression; signaling pathways; β-catenin.

Figure 1

Current knowledge on the cell type/context-dependent regulation of NF-κB signaling by Wnt/β-catenin pathway. Boxes in red and green colors indicate negative and positive regulations, respectively. Box 1: inhibition of NF-κB nuclear translocation by β-catenin-mediated sequestration or upregulation of IκB; Box 2: downregulation of TLR4 expression by β-catenin; Box 3: repression of NF-κB target gene expression through recruitment of corepressor at NF-κB-binding elements; Box 4: downregulation of NF-κB target gene expression through inhibition of CBP-mediated acetylation of NF-κB; Box 5: induction of p38 activity and p38-mediated NF-κB activation by β-catenin; Box 6: promotion of βTrCP-mediated IκB degradation through transcriptional upregulation of CRDBP by Wnt/β-catenin and CRD-BP-mediated BTRC (βTrCP) mRNA stabilization; Box 7: induction of NF-κB activity through transcriptional upregulation of TNFRSF19 mRNA; and Box 8: enhancement of NF-κB target gene expression through cooperation of β-catenin:TCF/LEF and NF-κB transcriptional complexes. PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular pattern molecules; β-Cat, β-catenin; P, phospho; ac, acetyl.

Figure 2

Current knowledge on the cell type/context-dependent regulation of Wnt/β-catenin signaling by NF-κB pathway. Boxes in red and green colors indicate negative and positive regulations, respectively. Box 1: inhibition of β-catenin nuclear translocation through NF-κB-induced transcriptional upregulation of LZTS2; Box 2: promotion of β-catenin degradation through NF-κB-induced transcriptional upregulation of Smurf; Box 3: promotion of β-catenin degradation by IKKβ; Box 4: reduction in Wnt/β-catenin target gene expression through sequestration of transcriptional co-factor p300 from β-catenin by NF-κB; Box 5: inhibition of β-catenin degradation by IKKα; Box 6: increase of β-catenin nuclear translocation by inhibition of LZTS2 expression by NF-κB; Box 7: enhancement of Wnt/β-catenin target gene expression through cooperation of NF-κB and β-catenin:TCF/LEF transcriptional complexes; and Box 8: enhancement of β-catenin:TCF/LEF transcriptional activity through transcriptional upregulation of Lef1 expression by NF-κB. PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular pattern molecules; β-Cat, β-catenin; P, phospho.