Sci. STKE, 15 May 2007
Wnt Signaling -catenin Activates ERK: Two Pathways for the Price of One
John F. Foley
Sciences STKE, AAAS, Washington, DC 20005, USA
Wnt/-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/-catenin signaling, such as Axin, result in the accumulation of -catenin in the nucleus. This leads to the increased expression of -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 -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 -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 -catenin. These data suggest that -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 -catenin. J. Biol. Chem. 282, 14482-14492 (2007). [Abstract] [Full Text]
Citation: J. F. Foley, -catenin Activates ERK: Two Pathways for the Price of One. Sci. STKE 2007, tw168 (2007).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882