![]() ![]() Of these, the most well-studied is SCF β-TrCP, a multiprotein complex that itself is regulated through the canonical Wnt signaling pathway ( 5, 6). β-Catenin is recognized and ubiquitinated by a growing number of E3 ligases. #ROZE SIAH PART 133 SERIAL#Polyubiquitination involves the serial action of E1, E2, and E3 enzymes, of which the substrate-recruiting E3 ligating enzymes are the most diverse. Defects in this protein degradation machinery or mutations in β-catenin that prevent the recognition or processing by this machinery often lead to the stabilization of β-catenin in its oncogenically active state ( 4). The most efficient means to lower the cellular levels of β-catenin is by polyubiquitination, leading to degradation in the 26 S proteasome. Not surprisingly, the level and cellular localization of β-catenin are tightly regulated by a finely tuned balance of post-translational modifications and protein turnover ( 1, 4). Mutations in β-catenin and its regulatory factors, such as adenomatous polyposis coli (APC), are associated with increased levels of nuclear β-catenin and in turn, to breast, colorectal, ovarian, and other cancers ( 1, 3, 4). Upon Wnt stimulation, β-catenin activates T cell factor (Tcf) 3/lymphoid enhancer factors (Lef) initiating the expression of many genes including cyclin D1, c-Myc, Axin2, and vascular endothelial growth factor (VEGF) ( 1). #ROZE SIAH PART 133 ACTIVATOR#Β-Catenin is a ubiquitous transcriptional activator in the canonical Wnt signaling pathway involved in cellular processes ranging from embryogenesis, cell proliferation, cell fate, and survival to adult stem cell differentiation and oncogenesis ( 1, 2). Siah-1 and TBL1 were found to bind to the same armadillo repeat domain of β-catenin, suggesting that polyubiquitination of β-catenin is regulated by competition between Siah-1 and TBL1 during Wnt signaling. In addition, TBL1 was shown to play a role in protecting β-catenin from Siah-1 ubiquitination in vitro and from Siah-1-targeted proteasomal degradation in cells. ![]() This study revealed that Siah-1 alone was able to polyubiquitinate β-catenin. Overexpression and purification protocols were developed for each of the SCF(TBL1) proteins, enabling a systematic analysis of β-catenin ubiquitination using an in vitro ubiquitination assay. Given the complexity of the various factors involved and the novelty of ubiquitination of the non-phosphorylated β-catenin substrate, we have investigated Siah-1-mediated ubiquitination of β-catenin in vitro and in cells. Upon UV-induced DNA damage, β-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and adenomatous polyposis coli (APC). Β-Catenin is a key component of the Wnt signaling pathway that functions as a transcriptional co-activator of Wnt target genes. ![]()
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