FAK and WNT Signaling: The Meeting of Two Pathways in Cancer and Development

Abstract

Recent studies connect the FAK and Wnt/β-catenin signaling pathways, both which promote cancer when aberrantly activated in mammalian cells. Over-stimulation of either Wnt/β-catenin or FAK activities was independently shown to promote numerous types of human cancers, including colon, breast, prostate and ovary. Observations in different model systems suggest a complex and dynamic cross-talk between these two pathways. During early vertebrate development, FAK protein is required for the proper regulation of Wnt/β- catenin signaling that controls pattern formation in the developing nervous system. In Xenopus laevis embryos, FAK protein depletion eliminated Wnt3a gene expression in the neural plate. In mouse osteoclast cells, mechanical stimulation through FAK activation stabilized β-catenin protein to promote its nuclear translocation. In contrast, in the mouse intestine, FAK activity was induced downstream of Wnt to promote intestinal regeneration and was also essential for tumorigenesis in an APC deletion model of colorectal cancer. Adding to this complexity, in human cell lines, FAK induced a context-dependent modulation of Wnt signaling to activate target-gene expression. Other diseases are also associated with FAK and Wnt pathway over-activation. Increased FAK and Wnt pathway activities were independently implicated in idiopathic pulmonary fibrosis (IPF), a lung disease of unknown etiology. Revealing the FAK-Wnt connection in IPF could provide a better understanding of disease pathology. There appear to be multiple interactions between the Wnt/β-catenin and FAK signaling pathways in different cell types and organisms. Mutual FAK-Wnt pathway regulation could be a general phenomenon, having many still undetermined roles in either normal physiological or disease processes.

Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

“…In addition, overexpression of beta-catenin and β-catenin/Wnt signaling is associated with many cancers including colorectal carcinomas [13,16,20,21]. Accordingly, we tested whether mAR activation alters beta-catenin gene expression.…”

“…Various proto-oncogenes, including c-Src, and GSK-3/ beta-catenin/ Wnt signaling have previously been described to be actively implicated in the regulation of colorectal tumors [13,14,15,16]. Since a prominent biological response to mAR activation in colon tumors is apoptotic regression [9,10], we have addressed in the present study the potential influence of membrane-initiated testosterone effects on the activity and/or expression of specific proto-oncogenes.…”

Aloe-emodin suppresses esophageal cancer cell TE1 proliferation by inhibiting AKT and ERK phosphorylation

“…Signal transduction pathways have an important role in tumorigenesis (45). Both AKT and ERK are important molecules in the MEK/ERK and PI3K/AKT signal transduction pathways (46,47).…”

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

“…Consistently, integrin-linked kinase knockdown was found to reduce ␤-catenin/TCF/LEF-dependent transcription in osteoblastic cells (41,42). In addition, integrin-mediated FAK activation may lead to PI3K/Akt activation and subsequent GSK-3␤ inhibition (43,44). Whether ␣5␤1 integrin activation can be linked to Wnt/␤-catenin signaling to control osteoblastogenesis has not been determined.…”