β-catenin Activates ERK: Two Pathways for the Price of One

Abstract

Wnt/β-catenin signaling is important for developmental processes, but this pathway is also associated with the development of certain cancers. Loss-of-function mutations in proteins involved in the negative regulation of Wnt/β-catenin signaling, such as Axin, result in the accumulation of β-catenin in the nucleus. This leads to the increased expression of β-catenin-responsive genes and to cellular proliferation. Dysregulation of the extracellular signal-regulated kinase (ERK) pathway, such as in the case of cells with mutations in ras , also leads to cancers. To investigate a possible link between these two pathways in carcinogenesis, Jeon et al . established an L929 fibroblast cell line in which production of Axin was inducible by the addition of doxycycline (L929-Axin). Western blot analysis revealed that the increased abundance of Axin in L929-Axin cells inhibited the accumulation of β-catenin, as expected, but also inhibited the phosphorylation of components of the ERK pathway, including Raf-1, MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), and ERK. L929-Axin cells showed a smaller proliferative response to epidermal growth factor (EGF) than did control cells, as measured by phosphorylation of Raf-1, MEK, and ERK. Flow-cytometry studies revealed that Axin also inhibited EGF-stimulated progression from the G1 to the S phase of the cell cycle. Negative regulation by Axin of the ERK pathway did not occur in cells containing a nondegradable mutant form of β-catenin. Ras, a small guanosine triphosphatase that responds to growth factor signals and activates the ERK pathway, was less abundant in L929-Axin cells than in control cells. This reduction in Ras (which was mediated by lysosomal degradation) did not occur in cells containing nondegradable β-catenin. These data suggest that β-catenin signaling can also activate the ERK signaling pathway, thereby enhancing the likelihood of carcinogenesis. S. H. Jeon, J.-Y. Yoon, Y.-N. Park, W.-J. Jeong, S. Kim, E.-H. Jho, Y.-J. Surh, K.-Y. Choi, Axin inhibits extracellular signal-regulated kinase pathway by Ras degradation via β-catenin. J. Biol. Chem. 282 , 14482-14492 (2007). [Abstract] [Full Text]