Department of Surgery
Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences
The stability and subcellular localization of beta-catenin, a protein that plays a major role in cell adhesion and proliferation, is tightly regulated by multiple signaling pathways. While aberrant activation of beta-catenin signaling has been implicated in cancers, the biochemical identity of transcriptionally active beta-catenin (ABC), commonly known as unphosphorylated serine 37 (S37) and threonine 41 (T41) beta-catenin, remains elusive. Our current study demonstrates that ABC transcriptional activity is influenced by phosphorylation of T120 by Protein Kinase D1 (PKD1). Whereas the nuclear beta-catenin from PKD1-low prostate cancer cell line C4-2 is unphosphorylated S37/T41/T120 with high transcription activity, the nuclear beta-catenin from PKD1-overexpressing C4-2 cells is highly phosphorylated at T120, S37 and T41 with low transcription activity, implying that accumulation of nuclear beta-catenin alone cannot be simply used as a read-out for Wnt activation. In human normal prostate tissue, the phosphorylated T120 beta-catenin is mainly localized to the trans-Golgi network (TGN, 22/30, 73%), and this pattern is significantly altered in prostate cancer (14/197, 7.1%), which is consistent with known down regulation of PKD1 in prostate cancer. These in vitro and in vivo data unveil a previously unrecognized post-translational modification of ABC through T120 phosphorylation by PKD1, which alters subcellular localization and transcriptional activity of beta-catenin. Our results support the view that beta-catenin signaling activity is regulated by spatial compartmentation and post-translational modifications and protein level of beta-catenin alone is insufficient to count signaling activity.
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Copyright: © 2012 Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Du C, Zhang C, Li Z, Biswas MHU, Balaji KC (2012) Beta-Catenin Phosphorylated at Threonine 120 Antagonizes Generation of Active Beta-Catenin by Spatial Localization in trans-Golgi Network. PLoS ONE 7(4): e33830. doi:10.1371/journal.pone.0033830. Link to article on publisher's site
Du, Cheng; Zhang, Chuanyou; Li, Zhuo; Biswas, Md Helal Uddin; and Balaji, Kethandapatti C., "Beta-catenin phosphorylated at threonine 120 antagonizes generation of active beta-catenin by spatial localization in trans-Golgi network" (2012). Open Access Articles. 2337.