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

J Cell Sci. 2018 May 22;131(10):jcs210575. doi: 10.1242/jcs.210575.


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 monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors 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 ubiquitylates TLE3 at wild-type levels in vitro, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAPT180A binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to 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.

Keywords: Apoptosis; GSK3; Phosphorylation; Ubiquitylation; Wnt; XIAP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Apoptosis Regulatory Proteins
  • Cell Line
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Threonine / metabolism*
  • Wnt Signaling Pathway
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism*
  • X-Linked Inhibitor of Apoptosis Protein / chemistry*
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*
  • Xenopus


  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Wnt3A Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Threonine
  • Glycogen Synthase Kinase 3