The E-cadherin/catenin complex and its impact on intracellular signaling pathways. Besides their function in adhesion, E-cadherin and its associated catenins are known modulators of several signaling pathways. (A) E-cadherin modulates canonical Wnt/β-catenin signaling. In the absence of Wnt, β-catenin gets phosphorylated by CKI and GSK-3β, which targets it for ubiquitination and proteasomal degradation.³⁰  Once Wnt binds its receptor Frizzled, β-catenin phosphorylation is inhibited, leading to β-catenin nuclear translocation and activation of TCF/LEF-dependent gene expression. E-cadherin expression is able to inhibit β-catenin signaling via sequestering this molecule to the E-cadherin cytoplasmic tail³¹  or to caveolin-1.³²  However, unbound E-cadherin might also stimulate Wnt/β-catenin signaling by assembling the Wnt signalosome, which phosphorylates E-cadherin and then releases β-catenin in the cytoplasm.³⁴  Interestingly, β-catenin functioning has been shown to instruct anti-inflammatory macrophages³⁵  and tolerogenic DCs.^36,37  (B) E-cadherin modulates PI3K/Akt signaling. Phosphatidylinositol 3-kinases (PI3K) phosphorylate protein kinase B (Akt), thereby regulating various processes. Depending on the context, the E-cadherin/catenin complex might stimulate this cascade by recruiting and activating PI3K at the E-cadherin/catenin complex,^39-44  or suppressing this cascade by recruiting PTEN to the E-cadherin/catenin complex.^45,46  PI3K/Akt signaling typically instructs anti-inflammatory activation of macrophages and DCs.^47,48  (C) The E-cadherin/catenin complex modulates Rho-family GTPases. The E-cadherin/catenin complex might bind and activate Rac-1, resulting in cytoskeletal reorganizations and cellular motility and adhesion. In addition, p120-catenin has been shown to modulate Rho GTPases, mainly via the inhibition of RhoA.^50-52  Of note, inhibitory effects of E-cadherin on Rho GTPase activity and cell motility have been reported.^55,56  Interestingly, macrophage and DC migration, adhesion, and T-cell stimulation are regulated by Rho-family GTPases, suggesting that E-cadherin expression might influence these phenomena. (D) The E-cadherin/catenin complex inhibits NF-κB. The transcription factor NF-κB is a master regulator of inflammatory gene regulation in macrophages and DCs.⁵⁹  At least in epithelial cells, the E-cadherin/catenin complex is a potent repressor of NF-κB functions, by recruiting this transcription factor to the complex, possibly with p120-catenin as docking site. Knocking down E-cadherin and p120 catenin results in massive NF-κB activation and inflammation.^56,60-63