Abstract
Wnt and EGFR signaling play key roles in embryonic development and cell proliferation. It is well documented that dysregulation of these two pathways often leads to tumorigenesis with poor prognosis. However, the possible crosstalk between the two pathways in cancer development is largely unknown. Although some reports show that EGFR might antagonize Wnt signaling during development in Drosophila, an increasing body of evidence indicates that Wnt and EGFR signaling crosstalk and transactivate one another in development and cancer. This review summarizes recent studies on the crosstalk between Wnt and EGFR signaling in cancers and points out several possible convergence points. Wnt ligands can activate EGFR signaling through their 7-transmembrane domain receptor Frizzled while EGFR can activate β-catenin via receptor tyrosine kinase-PI3K/Akt pathway; EGFR has been shown to form a complex with β-catenin and increase the invasion and metastasis of cancer cells. NKD2, a Wnt antagonist by interacting with Dishevelled, also escorts TGFα-containing exocytic vesicles to the basolateral membrane of polarized epithelial cells. Down-regulation of NKD2 causes Wnt activation and TGFα misdelivery, suggesting its functions in cell homeostasis and prevention of tumorigenesis.
Highlights
Tumorigenesis is a complex process requiring the accumulated alteration of multiple genes and pathways
All of these studies indicate that EGFR and bcatenin may be cooperating in tumorigenesis and that b-catenin might be a convergent point between EGFR and Wnt signaling in cancer development
We propose a model for the regulatory role of NKD2 in Wnt and EGFR signaling pathways: NKD2 binds to TGFa and escorts it to the plasma membrane, where TGFa gets released, and NKD2 binds to Dvl-1 and targets each other for mutual degradation
Summary
Tumorigenesis is a complex process requiring the accumulated alteration of multiple genes and pathways. In non-small cell lung cancers, EGFR mutations were significantly associated with a good prognosis in patients that had tumors with unmethylated Wnt antagonist genes, suggesting synchronous alterations of Wnt and EGFR signaling pathways are involved [47]. In liver-specific non-mutated b-catenin-overexpressing transgenic mice, EGFR seems to be a direct target of the activated Wnt signaling pathway, and EGFR activation might contribute to some mitogenic effect of increased b-catenin in the liver [56]. In liver-specific non-mutated b-catenin-overexpressing transgenic mice, EGFR seems to be a direct target of the pathway, and EGFR activation might contribute toward some mitogenic effects of increased b-catenin in the liver [56] All of these studies indicate that EGFR and bcatenin may be cooperating in tumorigenesis and that b-catenin might be a convergent point between EGFR and Wnt signaling in cancer development. NKD2 might be an important convergent point between Wnt and EGFR pathways to maintain the epithelial cell homeostasis
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