Professor Stephen Weiss and his colleagues from the University of Michigan have established functional links between canonical Wnt signaling, Slug expression, EMT and BRCA1 regulation. Published in the Proceedings of the National Academy of Sciences the work identifies an unrecognized Wnt/GSK3?/?-Trcp axis that controls Slug activity. Slug (Snail2) plays critical roles in regulating the epithelial-mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled has been unclear.
In the absence of Wnt signaling, Slug is phosphorylated by GSK3? and subsequently undergoes ? –Trcp dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3? kinase activity is inhibited, nuclear Slug levels increase and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels and reduced expression of the tumor suppressor, BRCA1, further studies demonstrate that Slug – as well as Snail – directly repress BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients.
MS Bioworks used a combination of LC-MS/MS with CID and ETD to identify phosphorylation sites on Slug.