Fig. 2

Cross-talk of the Wnt/β-catenin pathway with the RTK family receptors and its role in the induction of EMT. The Wnt/β-catenin and EGFR signaling pathways, on the binding of specific ligands, can activate each other. The binding of Wnt ligands with FZD receptors transactivates EGFR signaling by MMP-mediated release of EGF ligands. In turn, EGFR signaling transactivates the Wnt/β-catenin pathway through the PI3K/Akt and Ras/Raf/MEK/Erk signaling cascades. Akt can induce β-catenin by triggering its nuclear translocation or blocking GSK-3β activities. PTEN, which acts as a tumor suppressor and inhibits the activation of Akt, also negatively regulates β-catenin nuclear translocation. In addition, the aberrant activation of the EGFR pathway leads to an increase in free β-catenin accumulation in the cytoplasm through inducing dissociation from α-catenin. Several cell signaling pathways induce the expression of EMT-inducing transcription factors such as ZEB, SNAIL, and TWIST to push the tumor cells toward proliferation and metastasis. Moreover, the binding of several growth factors and cytokines to their receptors acts to induce the phosphorylation and activation of JAKs and activator of transcription proteins (STATs); STAT3/5 dimers stimulate the transcription of genes encoding EMT transcription factors, anti-apoptotic and survival proteins. In addition, in response to stimuli, such as TNF-α, the IKK complex is activated, resulting in phosphorylation of IKB and its degradation by the proteasome, and allowing the translocation of NF-κB into the nucleus