Cross-talk of WNT and FGF signaling pathways at GSK3ß to regulate ß-catenin and SNAIL signaling cascades

 Abstract

WNT and FGF signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (MMTV)-induced carcinogenesis, E2A-Pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. Canonical WNT signals are transduced through Frizzled receptor and LRP5/6 co-receptor to downregulate GSK3ß (GSK3B) activity not depending on Ser 9 phosphorylation. FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3ß activity depending on Ser 9 phosphorylation. Because GSK3ß-dependent phosphorylation of ß-catenin and SNAIL leads to FBXW1 (ßTRCP)-mediated ubiquitination and degradation, GSK3ß downregulation results in the stabilization and the nuclear accumulation of ß-catenin and SNAIL. Nuclear ß-catenin is complexed with TCF/LEF, Legless (BCL9 or BCL9L) and PYGO (PYGO1 or PYGO2) to activate transcription of CCND1, MYC, FGF18 and FGF20 genes for the cell-fate determination. Nuclear SNAIL represses transcription of CDH1 gene, encoding E-cadherin, to induce the epithelial-mesenchymal transition (EMT). Mammary carcinogenesis in MMTV-Wnt1 transgenic mice is accelerated by MMTV infection due to MMTV integration around Fgf3-Fgf4 or Fgf8 loci, and mammary carcinogenesis in MMTV-Fgf3 transgenic mice due to MMTV integration around Wnt1-Wnt10b locus. Co-activation of WNT and FGF signaling pathways in tumors leads to more malignant phenotypes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT and FGF signaling molecules could be utilized as screening method of cancer predisposition. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT and FGF signaling pathways could be developed as novel cancer-related biomarkers for diagnosis, prognosis, and therapy. Cocktail therapy using WNT and FGF inhibitors, such as small-molecule compounds and human neutralizing antibodies, should be developed to increase the efficacy of chemotherapy through the inhibition of recurrence by destructing cancer stem cells.

Full Text Options
Article
Metrics
 Share
 Info
Pages
1059 - 1064
doi
10.4161/cbt.5.9.3151
Type
Review
 Metrics
 Cite This Article
 Permissions
 Permissions
 Reprints
Cross-talk of WNT and FGF signaling pathways at GSK3ß to regulate ß-catenin and SNAIL signaling cascades