Wnt signals are transmitted through N-terminally dephosphorylated beta-catenin.
beta-catenin mediates Wnt signaling by acting as the essential co-activator for TCF transcription factors. Wnt signaling increases the half-life and therefore the absolute level of beta-catenin in responding cells. The current model states that these changes in beta-catenin stability set the threshold for Wnt signaling. However, we find that pharmacological inhibition of proteasome activity by ALLN leads to accumulation of cytosolic beta-catenin but not to increased TCF-mediated transcription. In addition, in temperature-sensitive ubiquitylation mutant CHO cells inhibition of ubiquitylation increases beta-catenin levels, but does not induce transcriptional activation of TCF reporter genes. Using an antibody specific for beta-catenin dephosphorylated at residues Ser37 and Thr41, we show that Wnt signals specifically increase the levels of dephosphorylated beta-catenin, whereas ALLN does not. We conclude that changes in the phosphorylation status of the N-terminus of beta-catenin that occur upon Wnt signaling independently affect the signaling properties and half-life of beta-catenin. Hence, Wnt signals are transduced via N-terminally dephosphorylated beta-catenin.
Staal
Frank J T
FJ
Department of Immunology, Erasmus University Rotterdam/University Hospital Rotterdam, The Netherlands.
van Noort
Mascha
M
Strous
Ger J
GJ
Clevers
Hans C
HC
D000818:Animals; D016466:CHO Cells; D002154:Calpain / Q000037:antagonists & inhibitors; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D007976:Leupeptins; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C063261:acetylleucyl-leucyl-norleucinal; D002154:Calpain