Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat552, increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat552 in the nucleus of inflamed and cancerous cells. Nuclear chromatin bound localization of LMW pβ-Cat552 was blocked in cells by inhibition of proteasomal chymotrypsin-like activity but not by other protease inhibitors. K48 polyubiquitinated FS and LMW β-catenin were increased by treatment with bortezomib. Overexpressed in vitro double truncated β-catenin increased transcriptional activity, cell proliferation and growth of tumor xenografts compared to FS β-catenin. Serine 552-> alanin substitution abrogated K48 polyubiquitination, β-catenin nuclear translocation and tumor xenograft growth. These data suggest that a novel proteasome-dependent posttranslational modification of β-catenin enhances transcriptional activation. Discovery of this pathway may be helpful in the development of diagnostic and therapeutic tools in colitis and cancer.
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This work was supported by Merit Review [Award # IO1CX001353 to TAB] from the United States (U.S.) Department of Veterans Affairs Clinical Sciences Research and Development Program; the National Institutes of Health [2R01DK095662-06A1 to TAB and R01CA175105to Q-BS]; National Institute Of Diabetes & Digestive & Kidney Diseases [U01DK085507 to LL], and the Training Program in Oncogenesis and Developmental Biology through the National Cancer Institute [NCI T32 CA080621, to support EMB].
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-017-18421-8.
Goretsky, Tatiana; Bradford, Emily M.; Ye, Qing; Lamping, Olivia F.; Vanagunas, Tomas; Moyer, Mary Pat; Keller, Patrick C.; Sinh, Preetika; Llovet, Josep M.; Gao, Tianyan; She, Qing-Bai; Li, Linheng; and Barrett, Terrence A., "Beta-Catenin Cleavage Enhances Transcriptional Activation" (2018). Internal Medicine Faculty Publications. 147.