Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling

Abstract

X-linked Inhibitor of Apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitination of the co-repressor Groucho/TLE, decreasing its affinity for TCF/Lef and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180 and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos. Although XIAPT180A ubiquitinates TLE3 at wild-type levels in vitro, it exhibits reduced capacity to ubiquitinate and bind TLE3 in human cells. XIAPT180A binds Smac and inhibits Fas-induced apoptosis to a similar degree as wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.